Aug 222014
 

Chemical structure for etirinotecan pegol

Etirinotecan pegol (NKTR-102)

848779-32-8

PEG-irinotecan

Also known as: NKTR-102; UNII-LJ16641SFT; 848779-32-8

Molecular Formula: C161H192N20O40   Molecular Weight: 3047.35718

Nektar Therapeutics innovator

http://www.acsmedchem.org/mediabstractf2013.pdf

CAS:  1193151-09-5

Synonym:   NKTR102; NKTR 102; NKTR-102; pegylated irinotecan NKTR 102; Etirinotecan pegol.

IUPAC/Chemical name: (1). Tetrakis{(4S)-9-[([1,4'-bipiperidinyl]-1′-carbonyl)oxy]-4,11-diethyl-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl} N,N’,N”,N”’- {methanetetrayltetrakis[methylenepoly(oxyethylene)oxy(1-oxoethylene)]}tetraglycinate tetrahydrochloride

(2). Poly(oxy-1,2-ethanediyl), α-hydro-ω-[2-[[2-[[(4S)-9-[([1,4'-bipiperidin]-1′-ylcarbonyl)oxy]- 4,11-diethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2- b]quinolin-4-yl]oxy]-2-oxoethyl]amino]-2-oxoethoxy]-, ether with 2,2-bis(hydroxymethyl)- 1,3-propanediol, hydrochloride (4:1:4)

Etirinotecan pegol tetratriflutate [USAN]

RN: 1193151-12-0

2D chemical structure of 1193151-12-0

MF and MW

  • 3503.4754

Tetrakis((4S)-9-(((1,4′-bipiperidinyl)-1′-carbonyl)oxy)-4,11-diethyl-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano(3′,4′:6,7)indolizino(1,2-b)quinolin-4-yl) N,N’,N”,N”’- (methanetetrayltetrakis(methylenepoly(oxyethylene)oxy(1-oxoethylene)))tetraglycinate tetrakis(trifluoroacetate)

NKTR-102 is currently being developed by Nektar. According to the company’s news release, this agent exhibits a very high response rate and excellent clinical benefit rate in patients with metastatic breast cancer, and importantly, this anti-tumor activity is maintained in each of the poor prognosis subsets within the study. The data from the Phase 2 study also shows highly promising PFS of 5.3 months and OS of 13.1 months in the every three week dose schedule, which was also very well-tolerated.   As a novel topoisomerase I inhibitor in breast cancer, NKTR-102 holds great therapeutic potential and allows us to address the challenge of resistance in this setting

NKTR-102 (PEG-irinotecan), a PEGylated form of irinotecan, is in clinical development by Nektar Therapeutics for the treatment of multiple solid tumors, including colorectal cancer, metastatic or locally advanced breast cancer, metastatic or locally advanced ovarian cancer and gastrointestinal cancer. No recent development has been reported for phase I clinical trials for the treatment of gastrointestinal cancer.

In preclinical studies, NKTR-102 resulted in significantly higher reduction in tumor growth than irinotecan in colon, lung and breast tumors. The company believes that following intravenous administration of NKTR-102, irinotecan will be released slowly, resulting in prolonged systemic exposure of irinotecan. Irinotecan is a cytotoxic anticancer agent used extensively to treat colorectal, lung, esophageal and other solid tumors. In 2011, orphan drug designation was assigned to the compound in the U.S. for the treatment of ovarian cancer.

In 2011, orphan drug designation was assigned in the E.U. for the treatment of ovarian cancer. In 2012, fast track designation was assigned by the FDA for the treatment of locally recurrent or metastatic breast cancer progressing after treatment with an anthracycline, a taxane and capecitabine.

Therapeutic Area Nektar
Discovered
Indication Phase
Oncology
Etirinotecan pegol (NKTR-102)
Metastatic Breast Cancer
Phase 3
Platinum-Resistant Ovarian Cancer
Phase 2 Completed
Second-Line Colorectal Cancer
Phase 2 Completed
Bevacizumab (Avastin)-refractory high-grade glioma
Phase 2
Non-Small Cell Lung Cancer (NSCLC)
Phase 2
Small Cell Lung Cancer (SCLC)
Phase 2
GI and solid tumors
In combination with 5-FU

Phase 1 Completed

http://www.nektar.com/product_pipeline/all_phases.html#BAX855

Market Overview

Etirinotecan pegol is in Phase 3 clinical development for patients with metastatic or locally recurrent breast cancer and Phase 2 clinical development for patients with solid tumor malignancies, including ovarian, colorectal, glioma, small cell and non-small cell lung cancers. Each year, approximately 5.3 million patients worldwide are diagnosed with one of these types of cancer.1

Etirinotecan Pegol Clinical Data and Product Profile

Etirinotecan pegol (NKTR-102) is the first long-acting topoisomerase I-inhibitor (Topo I) designed to concentrate in tumor tissue, provide sustained tumor suppression throughout the entire chemotherapy cycle, and to reduce the peak exposures that are associated with toxicities of other cytotoxics. Etirinotecan pegol was invented by Nektar using its advanced polymer conjugate technology platform, and is the first oncology product candidate to leverage Nektar’s releasable polymer technology platform.

Topo I-inhibitors are important chemotherapeutic agents used to treat cancer. Immediately after dosing, however, standard topo I-inhibitors reach high peak concentrations and diffuse quickly throughout the body—penetrating and damaging healthy tissue, such as bone marrow, as well as tumor tissue. Subsequent rapid metabolism limits topo I exposure in tumor cells, reducing the duration of their effect and resulting in a much lower tumor exposure to the active metabolite that may limit their efficacy.

Etirinotecan pegol is a novel chemotherapeutic designed to enhance the anti-cancer effects of topo I-inhibition while minimizing its toxicities. Unlike first generation topo I-inhibitors that exhibit a high initial peak concentration and short half-life, etirinotecan pegol’s unique pro-drug design results in a lowered initial peak concentration of active topo I inhibitor in the blood. The large etirinotecan pegol molecule is inactive when administered. Over time, the body’s natural enzymatic processes slowly metabolize the linkers within the molecule, continuously freeing active drug that then works to stop tumor cell division through inhibition of topo I.

Clinical and preclinical studies have shown that the half-life of active drug generated from etirinotecan pegol is greatly extended to 50 days (compared to 48 hours for irinotecan) and that active drug remains in circulation throughout the entire chemotherapy cycle, providing sustained exposure to topo I inhibition. In preclinical models, etirinotecan pegol achieved a 300-fold increase in tumor concentration as compared to a first generation topo I-inhibitor. Because etirinotecan pegol is a large molecule, it is believed to penetrate the leaky vasculature within the tumor environment more readily than normal vasculature, concentrating and trapping etirinotecan pegol in tumor tissue.

Etirinotecan pegol is currently in development for the treatment of breast, ovarian, colorectal, glioma, small cell and non-small cell lung cancers.

Ongoing clinical development for etirinotecan pegol:

  • In metastatic breast cancer, a Phase 3 randomized, head to head study (The BEACON Study) of etirinotecan pegol compared to Treatment of Physician’s Choice (TPC) completed enrollment of 864 patients in August 2013. Data from the study on the primary endpoint of overall survival is expected by the end of 2014 or early 2015.
  • In ovarian cancer, an expanded Phase 2 study of single-agent etirinotecan pegol in platinum refractory/resistant ovarian cancer in 177 women who failed prior Doxil therapy was completed at the end of 2012.
  • In colorectal cancer, a 174-patient Phase 2 randomized, head-to-head study of etirinotecan pegol compared to irinotecan in patients with second-line colorectal cancer with the KRAS gene mutation is in progress.
  • Etirinotecan pegol is also being evaluated in glioma, small cell and non-small cell lung cancers.

Highlighted Data Presentations:

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were published in the November 2013 issue of The Lancet Oncology (click here to view manuscript) These data were previously presented at the 2011 ASCO Annual meeting (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in platinum-resistant/refractory ovarian cancer were published in the September 30, 2013 online edition of the Journal of Clinical Oncology (click here to view abstract). These data were previously presented at the 2010 ASCO Meeting (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were presented in an oral abstract session at the 2011 ASCO Breast Cancer Symposium by Agustin Garcia, MD. View presentation slides.

Data from a Phase 2 clinical study of NKTR-102 in a subpopulation of patients with platinum-resistant/refractory ovarian cancer and prior Doxil® (pegylated liposomal doxorubicin or PLD) treatment were presented at the 2011 ASCO Annual Meeting by Agustin Garcia, MD. (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were presented at the 2010 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium by Amad Awada, MD. (click here to download this presentation).

January 16-18, 2014 2014 Gastrointestinal Cancers SymposiumPoster C55: “A phase I study of etirinotecan pegol in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.” January 18, 2014 San Francisco, CA
February 22, 2014 26.2 with Donna Marathon sponsored by Mayo Clinic Jacksonville, FL
March 5-7, 2014 TAT 2013: International Congress on Targeted Anticancer Therapies Washington, DC
April 5-9, 2014 AACR Annual Meeting 2013 San Diego, CA
May 19-21, 2014 10th International Symposium on Polymer Therapeutics Valencia, Spain
May 30-June 3, 2014 2014 ASCO 50th Annual MeetingPoster Presentation: “Combination Immunotherapy: Synergy of a Long-Acting Engineered Cytokine (NKTR-214) and Checkpoint Inhibitors Anti-CTLA-2 or Anti-PD-1 in Murine Tumor Models,” Kantak et al.
Abstract Number: 3082
Session Title/Track: Developmental Therapies – Immunotherapy
Date: June 1, 2014, 8:00 a.m. – 11:45 a.m. Central Time
Chicago, Illinois
September 4-6, 2014 ASCO Breast Cancer Symposium San Francisco, CA
September 26-30, 2014 ESMO 2014 Congress Madrid, Spain
December 9-13, 2014 San Antonio Breast Cancer Symposium San Antonio, TX

 

……………………….

http://www.google.com.ar/patents/US7744861?cl=pt-PT

Example 1 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-20K

A. Synthesis of t-Boc-Glycine-Irinotecan

 

In a flask, 0.1 g Irinotecan (0.1704 mmoles), 0.059 g t-Boc-Glycine (0.3408 mmoles), and 0.021 g DMAP (0.1704 mmoles) were dissolved in 13 mL of anhydrous dichloromethane (DCM). To the solution was added 0.070 g DCC (0.3408 mmoles) dissolved in 2 mL of anhydrous DCM. The solution was stirred overnight at room temperature. The solid was removed through a coarse frit, and the solution was washed with 10 mL of 0.1N HCL in a separatory funnel. The organic phase was further washed with 10 mL of deionized H2O in a separatory funnel and then dried with Na2SO4. The solvent was removed using rotary evaporation and the product was further dried under vacuum. 1H NMR (DMSO): δ 0.919 (t, CH2CH 3), 1.34 (s, C(CH3)3), 3.83 (m, CH2), 7.66 (d, aromatic H).

B. Deprotection of t-Boc-Glycine-Irinotecan

 

0.1 g t-Boc-Glycine-Irinotecan (0.137 mmoles) was dissolved in 7 mL of anhydrous DCM. To the solution was added 0.53 mL trifluoroacetic acid (6.85 mmoles). The solution was stirred at room temperature for 1 hour. The solvent was removed using rotary evaporation. The crude product was dissolved in 0.1 mL MeOH and then precipitated in 25 mL of ether. The suspension was stirred in an ice bath for 30 minutes. The product was collected by filtration and dried under vacuum. 1H NMR (DMSO): δ 0.92 (t, CH2CH 3), 1.29 (t, CH2CH 3), 5.55 (s, 2H), 7.25 (s, aromatic H).

C. Covalent Attachment of a Multi-Armed Activated Polymer to Glycine Irinotecan.

 

0.516 g Glycine-Irinotecan (0.976 mmoles), 3.904 g 4arm-PEG(20K)-CM (0.1952 mmoles), 0.0596 g 4-(dimethylamino)pyridine (DMAP, 0.488 mmoles), and 0.0658 g 2-hydroxybenzyltriazole (HOBT, 0.488 mmoles) were dissolved in 60 mL anhydrous methylene chloride. To the resulting solution was added 0.282 g 1,3-dicyclohexylcarbodiimide (DCC, 1.3664 mmoles). The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a coarse frit and the solvent was removed using rotary evaporation. The syrup was precipitated in 200 mL of cold isopropanol over an ice bath. The solid was filtered and then dried under vacuum. Yield: 4.08 g. 1H NMR (DMSO): δ 0.909 (t, CH2CH 3), 1.28 (m, CH2CH 3), 3.5 (br m, PEG), 3.92 (s, CH2), 5.50 (s, 2H).

Example 2 ANTI-TUMOR ACTIVITY OF PENTAERYTHRITOLYL-4-ARM-(PEG -1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-20K, “4-ARM-PEG-GLY-IRINO-20K” IN A COLON CANCER MOUSE XENOGRAFT MODEL

Human HT29 colon tumor xenografts were subcutaneously implanted in athymic nude mice. After about two weeks of adequate tumor growth (100 to 250 mg), these animals were divided into different groups of ten mice each. One group was dosed with normal saline (control), a second group was dosed with 60 mg/kg of irinotecan, and the third group was dosed with 60 mg/kg of the 4-arm PEG-GLY-Irino-20K (dose calculated per irinotecan content). Doses were administered intraveneously, with one dose administered every 4 days for a total of 3 administered doses. The mice were observed daily and the tumors were measured with calipers twice a week. FIG.1 shows the effect of irinotecan and PEG-irinotecan treatment on HT29 colon tumors in athymic nude mice.

As can be seen from the results depicted in FIG. 1, mice treated with both irinotecan and 4-arm-PEG-GLY-Irino-20K exhibited a delay in tumor growth (anti-tumor activity) that was significantly improved when compared to the control. Moreover, the delay in tumor growth was significantly better for the 4-arm-PEG-GLY-Irino-20K group of mice when compared to the group of animals administered unconjugated irinotecan.

Example 3 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-40K, “4-ARM-PEG-GLY-IRINO-40K”

4-arm-PEG-GLY-IRINO-40K was prepared in an identical fashion to that described for the 20K compound in Example 1, with the exception that in step C, the multi-armed activated PEG reagent employed was 4 arm-PEG(40K)-CM rather than the 20K material.

Example 4 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-SN-38)-20K, “4-ARM-PEG-GLY-SN-38-20K”

4-arm PEG-GLY-SN-38-20K was prepared in a similar fashion to its irinotecan counterpart as described in Example 1, with the exception that the active agent employed was SN-38, an active metabolite of camptothecin, rather than irinotecan, where the phenolic-OH of SN-38 was protected with MEMCI (2-methoxyethoxymethyl chloride) during the chemical transformations, followed by deprotection with TEA to provide the desired multi-armed conjugate.

Example 5 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-SN-38)-40K, “4-ARM-PEG-GLY-SN-38-40K”

4-arm PEG-GLY-SN-38-40K was prepared in a similar fashion to the 20K version described above, with the exception that the multi-armed activated PEG reagent employed was 4 arm-PEG(40K)-CM rather than the 20K material.

Example 8 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-2-{2-[2-1-HYDROXY-2-OXO-VINYLOXY)-ETHOXY]-ETHYLAMINO}-PROPEN-1-ONE LINKED-IRINOTECAN)-20K AND -40K

 

A. 2-(2-t-Boc-aminoethoxy)ethanol (1)

2-(2-Aminoethoxy)ethanol (10.5 g, 0.1 mol) and NaHCO3 (12.6 g, 0.15 mol) were added to 100 mL CH2Cl2 and 100 mL H2O. The solution was stirred at RT for 10 minutes, then di-tert-butyl dicarbonate (21.8 g, 0.1 mol) was added. The resulting solution was stirred at RT overnight, then extracted with CH2Cl2 (3×100 mL). The organic phases were combined and dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was subjected to silica gel column chromatography (CH2Cl2:CH3OH=50:1˜10:1) to afford 2-(2-t-Boc-aminoethoxy)ethanol (1) (16.0 g, 78 mmol, yield 78%)

B. 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-Irinotecan (2)

2-(2-t-Boc-aminoethoxy)ethanol (1) (12.3 g, 60 mmol) and 4-dimethylaminopyridine (DMAP) (14.6 g, 120 mmol) were dissolved in 200 ml anhydrous CH2Cl2. Triphosgene (5.91 g, 20 mmol) was added to the solution while stirring at room temperature. After 20 minutes, the solution was added to a solution of irinotecan (6.0 g, 10.2 mmol) and DMAP (12.2 g, 100 mmol) in anhydrous CH2Cl2 (200 mL). The reaction was stirred at RT for 2 hrs, then washed with HCI solution (pH=3, 2L) to remove DMAP. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was evaporated under vacuum and subjected to silica gel column chromatography (CH2Cl2:CH3OH=40:1˜10:1) to afford 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (2) (4.9 g, 6.0 mmol, yield 59%).

C. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3)

2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (2) (4.7 g, 5.75 mmol) was dissolved in 60 mL CH2Cl2, and trifluoroacetic acid (TFA) (20 mL) was added at RT. The reaction solution was stirred for 2 hours. The solvents were removed under vacuum and the residue was added to ethyl ether and filtered to give a yellow solid as product 3 (4.3 g, yield 90%).

D. 4-arm-PEG20k-carbonate-inotecan (4)

4-arm-PEG20k-SCM (16.0 g) was dissolved in 200 mL CH2Cl2. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3) (2.85 g, 3.44 mmol) was dissolved in 12 mL DMF and treated with 0.6 mL TEA, then added to a solution of 4-arm-PEG20k-SCM. The reaction was stirred at RT for 12 hrs then precipitated in Et2O to yield a solid product, which was dissolved in 500 mL IPA at 50° C. The solution was cooled to RT and the resulting precipitate collected by filtration to give 4-arm-PEG20k-glycine -irinotecan (4) (16.2 g, drug content 7.5% based on HPLC analysis). Yield: 60%.

E. 4-arm-PEG40k-carbonate-irinotecan (5)

4-arm-PEG40k-SCM (32.0 g) was dissolved in 400 mL CH2Cl2. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3) (2.85 g, 3.44 mmol) was dissolved in 12 mL DMF and treated with 0.6 mL TEA, then added to the solution of 4-arm -PEG40k-SCM. The reaction was stirred at RT for 12 hrs and then precipitated in Et2O to get solid product, which was dissolved in 1000 mL isopropyl alcohol (IPA) at 50° C. The solution was cooled to RT and the precipitate collected by filtration to gave 4-arm-PEG40k-glycine-irinotecan (4) (g, drug content 3.7% based on HPLC analysis). Yield: 59%.

 

References

1: Iwase Y, Maitani Y. Dual functional octreotide-modified liposomal irinotecan leads to high therapeutic efficacy for medullary thyroid carcinoma xenografts. Cancer Sci. 2011 Oct 24. doi: 10.1111/j.1349-7006.2011.02128.x. [Epub ahead of print] PubMed PMID: 22017398.

2: Matsuzaki T, Takagi A, Furuta T, Ueno S, Kurita A, Nohara G, Kodaira H, Sawada S, Hashimoto S. Antitumor activity of IHL-305, a novel pegylated liposome containing irinotecan, in human xenograft models. Oncol Rep. 2012 Jan;27(1):189-97. doi: 10.3892/or.2011.1465. Epub 2011 Sep 20. PubMed PMID: 21935577.

3: Cobleigh MA. Other options in the treatment of advanced breast cancer. Semin Oncol. 2011 Jun;38 Suppl 2:S11-6. Review. PubMed PMID: 21600380.

4: Li C, Cui J, Wang C, Li Y, Zhang L, Xiu X, Li Y, Wei N, Zhang L, Wang P. Novel sulfobutyl ether cyclodextrin gradient leads to highly active liposomal irinotecan formulation. J Pharm Pharmacol. 2011 Jun;63(6):765-73. doi: 10.1111/j.2042-7158.2011.01272.x. Epub 2011 Apr 7. PubMed PMID: 21585373.

5: Iwase Y, Maitani Y. Octreotide-targeted liposomes loaded with CPT-11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma. Mol Pharm. 2011 Apr 4;8(2):330-7. Epub 2011 Jan 18. PubMed PMID: 21166471.

6: Xenidis N, Vardakis N, Varthalitis I, Giassas S, Kontopodis E, Ziras N, Gioulbasanis I, Samonis G, Kalbakis K, Georgoulias V. Α multicenter phase II study of pegylated liposomal doxorubicin in combination with irinotecan as second-line treatment of patients with refractory small-cell lung cancer. Cancer Chemother Pharmacol. 2011 Jul;68(1):63-8. Epub 2010 Sep 10. PubMed PMID: 20830475.

7: Pastorino F, Loi M, Sapra P, Becherini P, Cilli M, Emionite L, Ribatti D, Greenberger LM, Horak ID, Ponzoni M. Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor. Clin Cancer Res. 2010 Oct 1;16(19):4809-21. Epub 2010 Aug 11. PubMed PMID: 20702613.

8: Morgensztern D, Baggstrom MQ, Pillot G, Tan B, Fracasso P, Suresh R, Wildi J, Govindan R. A phase I study of pegylated liposomal doxorubicin and irinotecan in patients with solid tumors. Chemotherapy. 2009;55(6):441-5. Epub 2009 Dec 8. PubMed PMID: 19996589.

9: Meckley LM, Neumann PJ. Personalized medicine: factors influencing reimbursement. Health Policy. 2010 Feb;94(2):91-100. Epub 2009 Oct 7. PubMed PMID: 19815307.

10: Skak K, Søndergaard H, Frederiksen KS, Ehrnrooth E. In vivo antitumor efficacy of interleukin-21 in combination with chemotherapeutics. Cytokine. 2009 Dec;48(3):231-8. Epub 2009 Aug 25. PubMed PMID: 19709902.

11: Murphy CG, Seidman AD. Evolving approaches to metastatic breast cancer previously treated with anthracyclines and taxanes. Clin Breast Cancer. 2009 Jun;9 Suppl 2:S58-65. Review. PubMed PMID: 19596644.

12: Fox ME, Guillaudeu S, Fréchet JM, Jerger K, Macaraeg N, Szoka FC. Synthesis and in vivo antitumor efficacy of PEGylated poly(l-lysine) dendrimer-camptothecin conjugates. Mol Pharm. 2009 Sep-Oct;6(5):1562-72. PubMed PMID: 19588994; PubMed Central PMCID: PMC2765109.

13: Atyabi F, Farkhondehfai A, Esmaeili F, Dinarvand R. Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice. Acta Pharm. 2009 Jun;59(2):133-44. PubMed PMID: 19564139.

14: Liu Z, Robinson JT, Sun X, Dai H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J Am Chem Soc. 2008 Aug 20;130(33):10876-7. Epub 2008 Jul 29. PubMed PMID: 18661992; PubMed Central PMCID: PMC2597374.

15: Scott LC, Yao JC, Benson AB 3rd, Thomas AL, Falk S, Mena RR, Picus J, Wright J, Mulcahy MF, Ajani JA, Evans TR. A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma. Cancer Chemother Pharmacol. 2009 Jan;63(2):363-70. Epub 2008 Apr 9. PubMed PMID: 18398613.

16: Almubarak M, Newton M, Altaha R. Reinduction of bevacizumab in combination with pegylated liposomal Doxorubicin in a patient with recurrent glioblastoma multiforme who progressed on bevacizumab/irinotecan. J Oncol. 2008;2008:942618. Epub 2008 Sep 2. PubMed PMID: 19259336; PubMed Central PMCID: PMC2648641.

17: Krauze MT, Noble CO, Kawaguchi T, Drummond D, Kirpotin DB, Yamashita Y, Kullberg E, Forsayeth J, Park JW, Bankiewicz KS. Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts. Neuro Oncol. 2007 Oct;9(4):393-403. Epub 2007 Jul 24. PubMed PMID: 17652269; PubMed Central PMCID: PMC1994096.

18: Li YF, Fu S, Hu W, Liu JH, Finkel KW, Gershenson DM, Kavanagh JJ. Systemic anticancer therapy in gynecological cancer patients with renal dysfunction. Int J Gynecol Cancer. 2007 Jul-Aug;17(4):739-63. Epub 2007 Feb 16. Review. PubMed PMID: 17309673.

19: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2006 Dec;28(10):719-40. PubMed PMID: 17235418.

20: Lokich J. Same-day pegfilgrastim and chemotherapy. Cancer Invest. 2005;23(7):573-6. PubMed PMID: 16305982.

21: Honig A, Rieger L, Sutterlin A, Kapp M, Dietl J, Sutterlin MW, Kämmerer U. Brain metastases in breast cancer–an in vitro study to evaluate new systemic chemotherapeutic options. Anticancer Res. 2005 May-Jun;25(3A):1531-7. PubMed PMID: 16033055.

Irinotecan
Irinotecan.svg
Irinotecan ball-and-stick.png
Systematic (IUPAC) name
(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-
3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-
9-yl-[1,4’bipiperidine]-1’-carboxylate
Clinical data
Trade names Camptosar
AHFS/Drugs.com monograph
MedlinePlus a608043
Pregnancy cat. D (Australia, United States)
Legal status POM (UK), ℞-only (U.S.)
Routes Intravenous
Pharmacokinetic data
Bioavailability NA
Metabolism Hepatic glucuronidation
Half-life 6 to 12 hours
Excretion Biliary and renal
Identifiers
CAS number 100286-90-6 Yes
ATC code L01XX19
PubChem CID 60838
DrugBank DB00762
ChemSpider 54825 Yes
UNII 7673326042 Yes
KEGG D08086 Yes
ChEMBL CHEMBL481 Yes
Chemical data
Formula C33H38N4O6 e 
Mol. mass 586.678 g/mol (Irinotecan)
623.139 g/mol (Irinotecan hydrochloride)
677.185 g/mol (Irinotecan hydrochloride trihydrate))

…………..

Irinotecan (Camptosar, Pfizer; Campto, Yakult Honsha) is a drug used for the treatment of cancer.

Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1.[1] In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.

Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996[2] and full approval in 1998.[3] During development, it was known as CPT-11.

Mechanism

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:

IrinotecanPathway_WP46359

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IrinotecanPathway_WP46359

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Irinotecan Pathway edit

  1. The interactive pathway map can be edited at WikiPathways: “IrinotecanPathway_WP46359″.

Side-effects

The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune system.

Diarrhea

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or Lomotil with the first loose bowel movement.

Immunosuppression

The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia (a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.

Pharmacogenomics

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.

*28 variant patients

People with variants of the UGT1A1 called TA7, also known as the “*28 variant”, express fewer UGT1A1 enzymes in their liver and often suffer from Gilbert’s syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.[4]

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.[4]

In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses.[5] Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient’s genotype.[6]

Research

Recently it was shown that antitumor activity of irinotecan against glioblastoma can be enhanced by co-treatment with statins.[7] Similarly, it was shown that berberine may enhance chemosensitivity to irinotecan in colon cancercells. [8]

 

 

References

  1. Pommier, Y., Leo, E., Zhang, H., Marchand, C. 2010. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17: 421-433.
  2. New York Times Article http://www.nytimes.com/1996/06/18/science/new-cancer-drug-approved.html
  3. FDA Review Letter http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20571s8ltr.pdf
  4. Innocenti F, Undevia SD, Iyer L, et al. (April 2004). “Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan”. J. Clin. Oncol. 22 (8): 1382–8. doi:10.1200/JCO.2004.07.173. PMID 15007088.
  5. Camptosar® irinotecan hydrochloride injection August 2010 http://labeling.pfizer.com/ShowLabeling.aspx?id=533
  6. O’Dwyer PJ, Catalano RB (October 2006). “Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy”. J. Clin. Oncol. 24 (28): 4534–8. doi:10.1200/JCO.2006.07.3031. PMID 17008691.
  7. Jiang PF (Jan 2014). “Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs.”. J Transl Med. 12. doi:10.1186/1479-5876-12-13. PMC 3898565. PMID 24433351.
  8. Yu M (Jan 2014). “Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF-κB”. J Mol Med Rep 9 (1): 249–54. doi:10.3892/mmr.2013.1762. PMID 24173769.
  9. DNA Topoisomerases and Cancer. Yves Pommier, Editor. Human Press. 2012

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Aug 212014
 

Migalastat hydrochloride
CAS Number: 75172-81-5 hydrochloride

CAS BASE….108147-54-2

ABS ROT = (+)

+53.0 °
Conc: 1 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

IN Van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959 

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-

Molecular Structure:
Molecular Structure of 75172-81-5 (3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-)
Formula: C6H14ClNO4
Molecular Weight:199.63
Synonyms:  3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, (2R,3S,4R,5S)- (9CI);

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, [2R-(2a,3a,4a,5b)]-;

Migalastat hydrochloride;Galactostatin hydrochloride;

(2S,3R,4S,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride;

  • 1-Deoxygalactonojirimycin
  • 1-Deoxygalactostatin
  • Amigal
  • DDIG
  • Migalastat
  • UNII-C4XNY919FW

Melting Point:160-2 °C………http://www.google.com/patents/DE3906463A1?cl=de
Boiling Point:382.7 °C at 760 mmHg
Flash Point:185.2 °C

Amicus Therapeutics, Inc. innovator

Aug 2014

http://www.xconomy.com/new-york/2014/08/20/with-persistence-and-phase-3-win-amicus-nears-first-drug-approval/?utm_source=rss&utm_medium=rss&utm_campaign=with-persistence-and-phase-3-win-amicus-nears-first-drug-approval

Amicus Therapeutics was on the ropes in late 2012 when its pill for a rare condition called Fabry Disease108147-54-2 failed a late-stage trial. It had already put seven years of work into the drug, and the setback added even more development time and uncertainty to the mix. But the Cranbury, NJ-based company kept plugging away, and now it looks like all the effort could lead to its first approved drug.

Amicus (NASDAQ: FOLD) is reporting today that the Fabry drug, migalastat, succeeded in the second of two late-stage trials. It hit two main goals that essentially measured its ability to slow the decline of Fabry patients’ kidney function comparably to enzyme-replacement therapy (ERT)—the standard of care for the often-fatal disorder.

Amicus believes the results, along with those from an earlier Phase 3 trial comparing migalastat to a placebo, are good enough to ask regulators in the U.S. and Europe for market approval.

“These are the good days to be a CEO,” says Amicus CEO John Crowley (pictured above). “It’s great when a plan comes together and data cooperates.”

Crowley says Amicus will seek approval of migalastat first in Europe and is already in talks with regulators there. In the next few months, Amicus will begin talking with the FDA about a path for approval in the U.S. as well.

 

 

End feb 2013

About Amicus Therapeutics

Amicus Therapeutics  is a biopharmaceutical company at the forefront of therapies for rare and orphan diseases. The Company is developing orally-administered, small molecule drugs called pharmacological chaperones, a novel, first-in-class approach to treating a broad range of human genetic diseases. Amicus’ late-stage programs for lysosomal storage disorders include migalastat HCl monotherapy in Phase 3 for Fabry disease; migalastat HCl co-administered with enzyme replacement therapy (ERT) in Phase 2 for Fabry disease; and AT2220 co-administered with ERT in Phase 2 for Pompe disease.

About Migalastat HCl

Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in the United States and GSK has commercial rights to all of these products in the rest of world.

As a monotherapy, migalastat HCl is designed to bind to and stabilize, or “chaperone” a patient’s own alpha-galactosidase A (alpha-Gal A) enzyme in patients with genetic mutations that are amenable to this chaperone in a cell-based assay. Migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with genetic mutations that are amenable to this chaperone monotherapy in a cell-based assay. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 compares migalastat HCl to ERT to primarily support global registration.

For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form thereby allowing more active enzyme to reach tissues.2Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with JCR Pharmaceutical Co. Ltd’s proprietary investigational ERT (JR-051, recombinant human alpha-Gal A enzyme) is in preclinical development.

About Fabry Disease

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of α-Gal are called “substrates” of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.

It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.

1. Bichet, et al., A Phase 2a Study to Investigate the Effect of a Single Dose of Migalastat HCl, a Pharmacological Chaperone, on Agalsidase Activity in Subjects with Fabry Disease, LDN WORLD 2012

2. Benjamin, et al.Molecular Therapy: April 2012, Vol. 20, No. 4, pp. 717–726.

http://clinicaltrials.gov/show/NCT01458119

http://www.docstoc.com/docs/129812511/migalastat-hcl

 

Migalastat hydrochloride is a pharmacological chaperone in phase III development at Amicus Pharmaceuticals for the oral treatment of Fabry’s disease. Fabry’s disease occurs as the result of an inherited genetic mutation that results in the production of a misfolded alpha galactosidase A (alpha-GAL) enzyme, which is responsible for breaking down globotriaosylceramide (GL-3) in the lysosome. Migalastat acts by selectively binding to the misfolded alpha-GAL, increasing its stability and promoting proper folding, processing and trafficking of the enzyme from the endoplasmic reticulum to the lysosome.

In February 2004, migalastat hydrochloride was granted orphan drug designation by the FDA for the treatment of Fabry’s disease.

The EMEA assigned orphan drug designation for the compound in 2006 for the treatment of the same indication. In 2007, the compound was licensed to Shire Pharmaceuticals by Amicus Therapeutics worldwide, with the exception of the U.S., for the treatment of Fabry’s disease.

In 2009, this license agreement was terminated. In 2010, the compound was licensed by Amicus Therapeutics to GlaxoSmithKline on a worldwide basis to develop, manufacture and commercialize migalastat hydrochloride as a treatment for Fabry’s disease, but the license agreement terminated in 2013.

 

Chemical Name: DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE
Synonyms: DGJ;Amigal;Unii-cly7m0xd20;GALACTOSTATIN HCL;DGJ, HYDROCHLORIDE;Migalastat hydrochloride;Galactostatin hydrochloride;DEOXYGALACTONOJIRIMYCIN HCL;1-DEOXYGALACTONOJIRIMYCIN HCL;1,5-dideoxy-1,5-imino-d-galactitol

DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE Structure

 

………………………..

Links

http://www.google.co.in/patents/WO1999062517A1?cl=en

Example 1

A series of plant alkaloids (Scheme 1, ref. 9) were used for both in vitro inhibition and intracellular enhancement studies of α-Gal A activity. The results of inhibition experiments are shown in Fig. 1 A.

 

f^

 

Among the tested compounds, 1-deoxy-galactonojirimycin (DGJ, 5) known as a powerful competitive inhibitor for α-Gal A, showed the highest inhibitory activity with IC50 at 4.7 nM. α-3,4-Di-epi-homonojirimycin (3) was an effective inhibitor with IC50 at 2.9 μM. Other compounds showed moderate inhibitory activity with IC50 ranging from 0.25 mM (6) to 2.6 mM (2). Surprisingly, these compounds also effectively enhanced α-Gal A activity in COS-1 cells transfected with a mutant α-Gal A gene (R301Q), identified from an atypical variant form of Fabry disease with a residual α- Gal A activity at 4% of normal. By culturing the transfected COS-1 cells with these compounds at concentrations cat 3 – 10-fold of IC50 of the inhibitors, α-Gal A activity was enhanced 1.5 – 4-fold (Fig. 1C). The effectiveness of intracellular enhancement paralleled with in vitro inhibitory activity while the compounds were added to the culture medium at lOμM

concentration (Fig. IB).

………………………

Links

WO 2008045015

or  http://www.google.com/patents/EP2027137A1?cl=enhttp://www.google.com/patents/US7973157?cl=en

This invention relates to a process for purification of imino or amino sugars, such as D-1-deoxygalactonojirimycin hydrochloride (DGJ’HCl). This process can be used to produce multi-kilogram amounts of these nitrogen-containing sugars.

Sugars are useful in pharmacology since, in multiple biological processes, they have been found to play a major role in the selective inhibition of various enzymatic functions. One important type of sugars is the glycosidase inhibitors, which are useful in treatment of metabolic disorders. Galactosidases catalyze the hydrolysis of glycosidic linkages and are important in the metabolism of complex carbohydrates. Galactosidase inhibitors, such as D-I- deoxygalactonojirimycin (DGJ), can be used in the treatment of many diseases and conditions, including diabetes (e.g., U.S. Pat. 4,634,765), cancer (e.g., U.S. Pat. 5,250,545), herpes (e.g. , U.S. Pat. 4,957,926), HIV and Fabry Disease (Fan et al, Nat. Med. 1999 5:1, 112-5).

Commonly, sugars are purified through chromatographic separation. This can be done quickly and efficiently for laboratory scale synthesis, however, column chromatography and similar separation techniques become less useful as larger amounts of sugar are purified. The size of the column, amount of solvents and stationary phase (e.g. silica gel) required and time needed for separation each increase with the amount of product purified, making purification from multi-kilogram scale synthesis unrealistic using column chromatography.

Another common purification technique for sugars uses an ion- exchange resin. This technique can be tedious, requiring a tedious pre-treatment of the ion exchange resin. The available ion exchange resins are also not necessarily able to separate the sugars from salts (e.g., NaCl). Acidic resins tend to remove both metal ions found in the crude product and amino- or imino-sugars from the solution and are therefore not useful. Finding a resin that can selectively remove the metal cations and leave amino- or imino-sugars in solution is not trivial. In addition, after purification of a sugar using an ion exchange resin, an additional step of concentrating the diluted aqueous solution is required. This step can cause decomposition of the sugar, which produces contaminants, and reduces the yield.

U.S. Pats. 6,740,780, 6,683,185, 6,653,482, 6,653,480, 6,649,766, 6,605,724, 6,590,121, and 6,462,197 describe a process for the preparation of imino- sugars. These compounds are generally prepared from hydroxyl-protected oxime intermediates by formation of a lactam that is reduced to the hexitol. However, this process has disadvantages for the production on a multi-kg scale with regard to safety, upscaling, handling, and synthesis complexity. For example, several of the disclosed syntheses use flash chromatography for purification or ion-exchange resin treatment, a procedure that is not practicable on larger scale. One particularly useful imino sugar is DGJ. There are several DGJ preparations disclosed in publications, most of which are not suitable for an industrial laboratory on a preparative scale (e.g., >100 g). One such synthesis include a synthesis from D-galactose (Santoyo-Gonzalez, et al, Synlett 1999 593-595; Synthesis 1998 1787-1792), in which the use of chromatography is taught for the purification of the DGJ as well as for the purification of DGJ intermediates. The use of ion exchange resins for the purification of DGJ is also disclosed, but there is no indication of which, if any, resin would be a viable for the purification of DGJ on a preparative scale. The largest scale of DGJ prepared published is 13 g (see Fred-Robert Heiker, Alfred Matthias Schueller, Carbohydrate Research, 1986, 119-129). In this publication, DGJ was isolated by stirring with ion-exchange resin Lewatit MP 400 (OH) and crystallized with ethanol. However, this process cannot be readily scaled to multi- kilogram quantities.

Similarly, other industrial and pharmaceutically useful sugars are commonly purified using chromatography and ion exchange resins that cannot easily be scaled up to the purification of multi-kilogram quantities.

Therefore, there is a need for a process for purifying nitrogen- containing sugars, preferably hexose amino- or imino-sugars that is simple and cost effective for large-scale synthesis

FIG. 1. HPLC of purified DGJ after crystallization. The DGJ is over 99.5% pure.

 

 

FIG. 2A. 1H NMR of DGJ (post HCl extraction and crystallization), from 0 – 15 ppm in DMSO.

FIG. 2B. 1H NMR of DGJ (post HCl extraction and crystallization), from 0 – 5 ppm, in DMSO.

 

FIG. 3 A. 1H NMR of purified DGJ (after recrystallization), from 0 – 15 ppm, in D2O. Note OH moiety has exchanged with OD.

FIG. 3B. 1H NMR of purified DGJ (after recrystallization), from 0 -

4 ppm, in D2O. Note OH moiety has exchanged with OD.

 

FIG. 4. 13C NMR of purified DGJ, (after recrystallization), 45 – 76 ppm.

 

One amino-sugar of particular interest for purification by the method of the current invention is DGJ. DGJ, or D-l-deoxygalactonojirimycin, also described as (2R,3S,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine and 1- deoxy-galactostatin, is a noj irimycin (5-amino-5-deoxy-D-galactopyranose) derivative of the form:

Figure imgf000011_0001

Example 1: Preparation and Purification of DGJ

A protected crystalline galactofuranoside obtained from the technique described by Santoyo-Gonzalez. 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-α-D- galactofuranoside (1250 g), was hydrogenated for 1-2 days using methanol (10 L) with palladium on carbon (10%, wet, 44 g) at 50 psi of H2. Sodium methoxide (25% in methanol, 1.25 L) was added and hydrogenation was continued for 1-2 days at 100 psi ofH2. Catalyst was removed by filtration and the reaction was acidified with methanolic hydrogen chloride solution (20%, 1.9 L) and concentrated to give crude mixture of DGJ • HCl and sodium chloride as a solid. The purity of the DGJ was about 70% (w/w assay), with the remaining 30% being mostly sodium chloride.

The solid was washed with tetrahydrofuran (2 x 0.5 L) and ether (I x 0.5 L), and then combined with concentrated hydrochloric acid (3 L). DGJ went into solution, leaving NaCl undissolved. The obtained suspension was filtered to remove sodium chloride; the solid sodium chloride was washed with additional portion of hydrochloric acid (2 x 0.3 L). All hydrochloric acid solution were combined and slowly poured into stirred solution of tetrahydrofuran (60 L) and ether (11.3 L). The precipitate formed while the stirring was continued for 2 hours. The solid crude DGJ* HCl, was filtered and washed with tetrahydrofuran (0.5 L) and ether (2 x 0.5 L). An NMR spectrum is shown in FIGS. 2A-2B.

The solid was dried and recrystallized from water (1.2 mL /g) and ethanol (10 ml/1 ml of water). This recrystallization step may be repeated. This procedure gave white crystalline DGJ* HCl, and was usually obtained in about 70- 75% yield (320 – 345 g). The product of the purification, DGJ-HCl is a white crystalline solid, HPLC >98% (w/w assay) as shown in FIG. 1. FIGS. 3A-3D and FIG. 4 show the NMR spectra of purified DGJ, showing the six sugar carbons.

Example 2: Purification of 1-deoxymannojirimycin 1 -deoxymannojirimycin is made by the method described by Mariano

(J. Org. Chem., 1998, 841-859, see pg. 859, herein incorporated by reference). However, instead of purification by ion-exchange resin as described by Mariano, the 1-deoxymannojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the 1-deoxymannojirimycin hydrochloride is precipitated crystallized using solvents known for recrystallization of 1- deoxymannojirimycin (THF for crystallization and then ethanol/water.

Example 3: Purification of (+)-l-deoxynojirimycin

(+)-l-deoxynojirimycin is made by the method Kibayashi et al. (J. Org. Chem., 1987, 3337-3342, see pg. 334I5 herein incorporated by reference). It is synthesized from a piperidine compound (#14) in HCl/MeOH. The reported yield of 90% indicates that the reaction is essentially clean and does not contain other sugar side products. Therefore, the column chromatography used by Kibayashi is for the isolation of the product from non-sugar related impurities. Therefore, instead of purification by silica gel chromatography, the (+)-l-deoxynojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

Example 4: Purification of Nojirimycin

Nojirimycin is made by the method described by Kibayashi et al. (J.

Org. Chem., 1987, 3337-3342, see pg. 3342). However, after evaporating of the mixture at reduced pressure, instead of purification by silica gel chromatography with ammonia-methanol-chloroform as described by Kibayashi, the nojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the impurities not dissolved in HCl and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

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Links

Synthesis of (+)-1-deoxygalactonojirimycin and a related indolizidine
Tetrahedron Lett 1995, 36(5): 653

Amido-alcohol 1 is transformed via aminal 2 into 1-deoxygalactonojirimycin (3) and the structurally related indolizidine 4.

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Links

Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D-galactitol) starting from 1-deoxynojirimycin
Carbohydr Res 1990, 203(2): 314

………………………………..

Synthesis of (+)-1,5-dideoxy-1,5-imino-D-galactitol, a potent alpha-D-galactosidase inhibitor
Carbohydr Res 1987, 167: 305

 

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Links

SEE

Monosaccharides containing nitrogen in the ring, XXXVII. Synthesis of 1,5-didexy-1,5-imino-D-galactitol
Chem Ber 1980, 113(8): 2601

…………………………

Links

Org. Lett., 2010, 12 (17), pp 3957–3959
DOI: 10.1021/ol101556k

http://pubs.acs.org/doi/abs/10.1021/ol101556k

+53.0 °
Conc: 1 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

IN

van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959 

Abstract Image

The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction−transimination−sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.

http://pubs.acs.org/doi/suppl/10.1021/ol101556k/suppl_file/ol101556k_si_002.pdf

COMPD 18

D-galacto-1-deoxynojirimicin.HCl (18).

D-N-Boc-6-OBn-galacto-1-deoxynojirimicin (159 mg, 0.450 mmol) was dissolved in a mixture of MeOH
(10 mL) and 6 M HCl (2 mL). The flask was purged with argon, Pd/C-10% (20 mg) was added and a balloon
with hydrogen gas was placed on top of the reaction. The mixture was stirred overnight at room temperature.
Pd/C was removed by filtration and the filtrate evaporated to yield the crude product (90 mg, 100%) as a
white foam that needed no further purification.
[α]24D = + 53.0 (c = 1, H2O);

[lit4a [α]24D = +44.6 (c = 0.9, H2O); lit4b [α]20D = +46.1 (c = 0.9, H2O)].
HRMS calculated for [C6H13NO4 + H]+164.09173; Found 164.09160.
1H NMR (400 MHz, D2O) δ 4.20 (dd, J = 2.7, 1.1 Hz, 1H), 4.11 (ddd, J = 11.4, 9.7, 5.4 Hz, 1H), 3.88 (ddd,
J = 20.9, 12.2, 6.8 Hz, 2H), 3.68 (dd, J = 9.7, 3.0 Hz, 1H), 3.55 (dd, J = 12.5, 5.4 Hz, 1H), 3.46 (ddd, J = 8.6,
4.8, 1.0 Hz, 1H), 2.97 – 2.86 (t, J = 12.0 Hz, 1H). [lit4c supporting information contains 1
H NMR-spectrumof an authentic sample].
13C NMR (101 MHz, D2O) δ 73.01, 66.97, 64.69, 60.16, 59.15, 46.15

4a) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Núñez, F.; Pato, C.; Ojea, V. J. Org. Chem. 2008, 73, 2240
– 2255.

4b) Paulsen, H.; Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2601 – 2608. c)
McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69, 3565 – 3568.

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(- ) FORM………… BE CAREFUL

Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin
Org Lett 2010, 12(6): 1145

 http://pubs.acs.org/doi/abs/10.1021/ol100037c

Abstract Image

The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to α-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%.

Figure

Figure 1. Structures of nojirimycin (1) and DGJ (2).

SEE SUPP INFO

http://pubs.acs.org/doi/suppl/10.1021/ol100037c/suppl_file/ol100037c_si_001.pdf

(-)-1-deoxygalactojirimycin hydrochloride as transparent colorless needles.
[α]D -51.4 (D2O, c 1.0)

1H-NMR (D2O) δ ppm 4.09 (dd, 1H, J 2.9 Hz, 1.3 Hz), 4.00 (ddd, 1H, J = 11.3 Hz, 9.7 Hz, 5.3 Hz),
3.80 (dd, 1H, J = 12,1 Hz, 8.8 Hz), 3.73 (dd, 1H, J = 12.1 Hz, 8.8 Hz), 3.56 (dd, 1H, J = 9.7 Hz, 2.9
Hz), 3.44 (dd, 1H, J = 12.4 Hz, 5.3 Hz), 3.34 (ddd, 1H, J = 8.7 Hz, 4.8 Hz, 1.0 Hz), 2.8 (app. t, 1H,
J = 12.0 Hz)
13C-NMR (D2O, MeOH iSTD) δ 73.6, 67.5, 65.3, 60.7, 59.7, 46.7
HRMS Measured 164.0923 (M + H – Cl) Calculated 164.0923 (C6H13NO4 + H – Cl)

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Links

Concise and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin and its congeners using dioxanylpiperidene, a promising chiral building block
Org Lett 2003, 5(14): 2527

 http://pubs.acs.org/doi/abs/10.1021/ol034886y

Abstract Image

A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 13 was carried out via the use of 4in a highly stereocontrolled mode.

 

mp 135-135.5 °C [lit.3mp 137-139 °C];

[α]D25 +27.8° (c 0.67, H2O)
[lit.3[α]D23 +28° (c 0.5, H2O)];

1H NMR (300 MHz, D2O) δ 2.59–2.65 (m, 1H), 2.81–2.87 (m, 1H),
3.02–3.08 (m, 1H), 3.46–3.48 (m, 2H), 3.59–3.66 (m, 3H); 13C NMR (75 MHz, D2O) δ 44.7, 57.1,

58.4, 70.9, 71.4, 73.3 [lit4 13C NMR (125 MHz, D2O) δ 44.5, 56.8, 58.3, 70.1, 70.7, 72.3];

HRMScalcd for C6H13NO4 (M+) 163.0855, Found 163.0843. Anal. calcd for C6H13NO4: C, 44.16; N,
8.58; H, 8.03. Found: C, 44.31; N, 8.55; H, 7.71.

3. Schaller, C.; Vogel, P.; Jager, V. Carbohydrate Res. 1998, 314, 25-35.
4. Lee, B. W.; Jeong, Ill-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305-1309.

…………………………………………..

Links

Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: Five- versus six-membered ring formation
J Org Chem 2013, 78(19): 9791

http://pubs.acs.org/doi/abs/10.1021/jo401512h

Abstract Image

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

……………………………………………

Links

Ruiz, Maria; Journal of Organic Chemistry 2008, 73(6), 2240-2255 

http://pubs.acs.org/doi/abs/10.1021/jo702601z

ROT  +44.6 °  Conc: 0.9 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

Abstract Image

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the γ-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, hightrans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-l-altronojirimycin, 1-deoxy-d-gulonojirimycin, 1-deoxy-d-galactonojirimycin, 1-deoxy-l-idonojirimycin and 1-deoxy-d-talonojirimycin.

 

 

…………………..

Links

J. Org. Chem., 1991, 56 (2), pp 815–819
DOI: 10.1021/jo00002a057

http://pubs.acs.org/doi/abs/10.1021/jo00002a057

………………

Links

Hinsken, Werner; DE 3906463 A1 1990

http://www.google.com/patents/DE3906463A1?cl=de

Example 1 Preparation of 1,5-dideoxy-1,5-imino-D-glucitol hydrobromide

A suspension of 1,5-dideoxy-1,5-imino-D-glucitol (500 g) in isopropanol (2 l) with 48% hydrochloric acid, bromine (620 g). The suspension is stirred for 2 hours at 40 ° C, cooled to 0 ° C and the product isolated by filtration.

Yield: 700 g (93% of theory),
mp: 184 ° C.

Example 2 Preparation of 1,5-dideoxy-1,5-imino-D-mannitol hydrobromide

The prepared analogously to Example 1 from 1,5-dideoxy 1,5-imino-D-mannitol and 48% hydrobromic acid.

Yield: 89% of theory;

C₆H₁₄NO₄Br (244.1)
Ber .: C 29.5%; H 5.8%; N 5.7%; Br 32.7%;
vascular .: C 29.8%; H 5.8%; N 5.8%; Br 32.3%.

Example 3 Preparation of 1,5-dideoxy-1,5-imino-D-Galactitol- hydrochloride

The preparation was carried out analogously to Example 1 from 1,5-dideoxy-1,5-imino-D-galactitol and corresponding mole ratios of 37% hydrochloric acid.
yield: 91% of theory
, mp: 160-162 ° C.

 

Amat et al., “Eantioselective Synthesis of 1-deoxy-D-gluonojirimycin From A Phenylglycinol Derived Lactam,” Tetrahedron Letters, pp. 5355-5358, 2004.
2 Chernois, “Semimicro Experimental Organic Chemistry,” J. de Graff (1958), pp. 31-48.
3 Encyclopedia of Chemical Technology, 4th Ed., 1995, John Wiley & Sons, vol. 14: p. 737-741.
4 Heiker et al., “Synthesis of D-galacto-1-deoxynojirimycin (1, 5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin.” Carbohydrate Research, 203: 314-318, 1990.
5 Heiker et al., 1990, “Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin,” Carbohydrate Research, vol. 203: p. 314-318.
6 * Joseph, Carbohydrate Research 337 (2002) 1083-1087.
7 * Kinast et al. Angew. Chem. Int. Ed. Engl. 20 (1998), No. 9, pp. 805-806.
8 * Lamb, Laboratory Manual of General Chemistry, Harvard University Press, 1916, p. 108.
9 Linden et al., “1-Deoxynojirimycin Hydrochloride,” Acta ChrystallographicaC50, pp. 746-749, 1994.
10 Mellor et al., Preparation, biochemical characterization and biological properties of radiolabelled N-alkylated deoxynojirimycins, Biochem. J. Aug. 15, 2002; 366(Pt 1):225-233.
11 * Mills, Encyclopedia of Reagents for Organic Synthesis, Hydrochloric Acid, 2001 John Wily & Sons.
12 Santoyo-Gonzalez et al., “Use of N-Pivaloyl Imidazole as Protective Reagent for Sugars.” Synthesis 1998 1787-1792.
13 Schuller et al., “Synthesis of 2-acetamido-1, 2-dideoxy-D-galacto-nojirimycin (2-acetamido-1, 2, 5-trideoxy-1, 5-imino-D-galacitol) from 1-deoxynojirimycin.” Carbohydrate Res. 1990; 203: 308-313.
14 Supplementary European Search Report dated Mar. 11, 2010 issued in corresponding European Patent Application No. EP 06 77 2888.
15 Uriel et al., A Short and Efficient Synthesis of 1,5-dideoxy-1,5-imino-D-galactitol (1-deoxy-D-galactostatin) and 1,5-dideoxy-1,5-dideoxy-1,5-imino-L-altritol (1-deoxy-L-altrostatin) From D-galactose, Synlett (1999), vol. 5, pp. 593-595.

 

1-Deoxygalactonojirimycin:

(a) Liguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron200056, 5819−5833.

(b) Mehta, G.; Mohal, N. Tetrahedron Lett200041, 5741−5745.

(c) Asano, K.; Hakogi, T.; Iwama, S.; Katsumura, S. Chem. Commun1999, 41−42.

(d) Johnson, C. R.; Golebiowsky, A.; Sundram, H.; Miller, M. W.; Dwaihy, R. L. TetraherdonLett199536, 653−654.

(e) Uriel, C.; Santoyo-Gonzalez, F. Synlett 1999, 593−595.

(f) Ruiz, M.; Ruanova, T. M.; Ojea, V.; Quintela, J. M. Tetrahedron Lett199940, 2021−2024.

(g) Shilvock, J. P.; Fleet, G. W. J. Synlett 1998, 554−556.

(h) Chida, N.; Tanikawa, T.; Tobe, T.; Ogawa, S. J. Chem. Soc., Chem. Commun1994, 1247−1248.

(i) Aoyagi, S.; Fujimaki, S.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 199156, 815−819.

(j) Kajimoto, T.; Chen, L.; Liu, K. K. C.; Wong, C. H. J. Am. Chem. Soc1991113, 6678−6680.

(k) Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res1987167, 305−311. 1-Deoxyidonojirimycin:

(l) Singh, O. V.; Han, H. Tetrahedron Lett. 200344, 2387−2391.

(m) Schaller, C.; Vogel, P.; Jager, V. Carbohydr. Res1998314, 25−35.

(n) Fowler, P. A.; Haines, A. H.; Taylor, R. J. K.; Chrystal, E. J. T.; Gravestock, M. B. Carbohydr. Res1993,246 377−381.

(o) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C. H.J. Org. Chem199156, 6280−6289. 1-Deoxygulonojirimycin:  ref 5l.

(p) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 20013, 401−404.

(q) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M. Tetrahedron:  Asymmetry 200213, 795−799. (r) Liao, L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S. Tetrahedron:  Asymmetry 199910, 3649−3657.

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Effective technology selection for improving bioavailability (BA) can accelerate the development of promising compounds and reduce the overall cost and complexity of drug development. Science-based technology selection requires an understanding of the scientific fundamentals governing drug solubilization, absorption and metabolic fate, as well as the feasibility and performance boundaries between enabling technologies. Capsugel / Bend Research have developed a robust technology selection process facilitated by its breadth of BA-enhancing technologies and extensive experience in advancing hundreds of challenging compounds.

Published: 20-Aug-2014 | Format: PDF file  | Document type: White / Technical Paper

get it at

http://www.in-pharmatechnologist.com/smartlead/view/954647/4/Technology-Selection-To-Enhance-Oral-Bioavailability

 

 

 

 

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Aug 202014
 

 

 

 

Compassionate use is a treatment option that allows the use of an unauthorised medicine. Compassionate-use programmes are for patients in the European Union (EU) who have a disease with no satisfactory authorised therapies or cannot enter aclinical trial. They are intended to facilitate the availability to patients of new treatment options under development.

 

 

Compassionate-use programmes are often governed by legislation in individual EU Member States, to make medicines available on a named-patient basis or to cohorts of patients.

In addition to this, EU legislation provides an option for Member States to ask the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) to provide an opinion to all EU Member States on how to administer, distribute and use certain medicines for compassionate use. The CHMP also identifies which patients may benefit from compassionate-use programmes. This is described in Article 83 of Regulation (EC) No 726/2004External link icon and is complementary to national legislation.

 

 

The objectives of Article 83 are to:

  • facilitate and improve access to compassionate-use programmes by patients in the EU;
  • favour a common approach regarding the conditions of use, the conditions for distribution and the patients targeted for the compassionate use of unauthorised new medicines;
  • increase transparency between Member States in terms of treatment availability.

More information is available in:

 

 

Compassionate-use opinions from the CHMP

Name of medicine Ledipasvir/Sofosbuvir
Active substance ledipasvir, sofosbuvir
Dosage 90mg / 400 mg
Pharmaceutical form Film coated tablet
Member State notifying the Agency Ireland
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoringSummary on compassionate use
Date of opinion 20/02/2014
Company contact information Gilead Sciences Limited
Granta Park
Abington
Cambridgeshire
CB21 6GT
United Kingdom
Tel. +44 (0)208 5872206
Fax +44 (0)1223 897233
E-mail: eamemed.info@gilead.com
Status Ongoing
Related documents  -

 

Name of medicine Daclatasvir
Active substance daclatasvir
Dosage 30 and 60 mg
Pharmaceutical form Film coated tablet
Member State notifying the Agency Sweden
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoringSummary on compassionate use
Date of opinion 21/11/2013
Company contact information Bristol-Myers Squibb Pharma EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
Tel. +44 (0)1895 523 740
Fax +44 (0)1895 523 677
E-mail: medical.information@bms.com
Status Ongoing
Related documents  -

 

Name of medicine Sofosbuvir Gilead
Active substance Sofosbuvir
Dosage 400 mg
Pharmaceutical form Film-coated tablet
Member State notifying the Agency Sweden
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring
Summary on compassionate use
Date of opinion 24/10/2013
Company contact information Gilead Sciences International Ltd
Granta Park, Abington
Cambridgeshire CB21 6GT
United Kingdom
Tel. +44 (0)1223 897496
Fax +44 (0)1223 897233
E-mail: eamemed.info@gilead.com
Status Ongoing
Related documents  -

 

Name of medicine IV Zanamivir
Active substance Zanamivir
Dosage 10 mg/ml
Pharmaceutical form Solution for infusion
Member State notifying the Agency Sweden
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring
Summary on compassionate use
Date of opinion 18/02/2010
Company contact information GlaxoSmithKline Research & Development Limited
980 Great West Road, Brentford
Middlesex TW8 9GS
United Kingdom
Tel. +44 (0)20 8047 5000 or +44 (0)20 8990 3885
E-mail: julie.c.kerrison@gsk.com
Status Ongoing
Related documents  -

 

Name of product Tamiflu IV
Active substance Oseltamivir phosphate
Dosage 100 mg
Pharmaceutical form Powder for solution for infusion
Member State notifying the Agency Finland
CHMP opinion documents Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring
Summary on compassionate use
Date of opinion 20/01/2010
Company contact information F. Hoffmann-La Roche Ltd.
Pharmaceuticals Division
PBMV Bldg 74/3O 104
CH-4070, Basel
Switzerland
Tel. +41 61 688 5522
Fax +41 61 687 2239
E-mail: basel.tamifluquestions@roche.com
Status Closed
Related documents Public statement on Tamiflu IV: Closure of compassionate-use programme in the EU
Tamiflu IV compassionate-use programme EMEA/H/K/002287 – Closure of programme

 

 

Expanded access (also known as compassionate use) refers to the use of an investigational drug outside of a clinical trial by patients with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. Outside the US, such access is allowed through Named patient programs. In the US this type of access may be available, in accordance with United States Food and Drug Administration (FDA) regulations, when it is clear that patients may benefit from the treatment, the therapy can be given safely outside the clinical trial setting, no other alternative therapy is available, and the drug developer agrees to provide access to the drug. The FDA refers to such a program as an expanded access program (EAP).[1] EAPs can be leveraged in a wide range of therapeutic areas including HIV/AIDS and other infectious diseases, cancer, rare diseases, and cardiovascular diseases, to name a few.

There are several types of EAPs allowed in the United States. Treatment protocols and treatment INDs provide large numbers of patients access to investigational drugs. A single-patient IND is a request from a physician to the FDA that an individual patient be allowed access to an investigational drug on an emergency or compassionate use basis.[2] When the FDA receives a significant number of requests (~10 to 100) for individual patient expanded access to an investigational drug for the same use, they may ask the trial sponsor to consolidate these requests, creating an intermediate-size group.[3] “Compassionate use” is a more colloquial term that is not generally used by the FDA.

FDA regulations

Since 1987, the FDA has had rules in place that have enabled patients, under specific circumstances, to access drugs or biologics that are still in development for treatment purposes. These expanded access program rules were amended in 2009 by the FDA to ensure “broad and equitable access to investigational drugs for treatment.”[4]

The regulations include the following:[4]

  • Criteria that must be met in order to authorize the expanded access use
  • Requirements for expanded access submissions
  • Safeguards to protect patients and the clinical trial process

The regulations also include general criteria for granting expanded access:[3]

  • The patient must have a serious condition or disease for which there is no comparable alternative therapy available
  • The patient must be unable to participate in a clinical trial
  • The potential benefit must outweigh the potential risk of using the treatment
  • There should be no impact on the completion of the clinical trial or the drug’s approval

Despite the updated regulations, debate remains over key elements of expanded access:

  • Deciding at what point in the clinical trial process access should be given. Some stakeholders support expanded access programs after phase I testing in clinical trials. The FDA has stated that most drugs should not be eligible until some point during phase III when efficacy data have been obtained, unless compelling phase II data on safety and efficacy are available.[3][5]
  • Weighing risks to the patient against the potential benefits. The FDA requires that a physician and an institutional review board (IRB) determine that a treatment will not pose undue risk to the patient, relative to the condition he or she is suffering from.[6] However, the FDA maintains the right to overrule the physician and IRB.[3]
  • Determining who should get access. The FDA states that expanded access should only be considered for patients with a serious disease or condition, but the FDA’s rules do not provide a definition of “serious”; instead it provides examples of diseases and conditions that fall into this category.[3] In the case of a cancer drug, the sponsor of an expanded access program must define exactly which patients will get access. Most often, access is limited to those patients with the same type of cancer the drug is being tested for.[7]

A number of challenges can exist when patients seek access to investigational drugs:

  • Obtaining an IRB review. Finding time on an IRB’s schedule can be difficult, particularly for doctors who are not based at research centers where IRBs are readily available. The fee for the review may pose a problem as well. It may be unclear who is responsible for the cost of the IRB review, which can be as much as $2,000. Many IRBs conduct reviews pro bono but others that charge will often only waive their fees for research done in their hospital.[6][8]
  • Protecting physicians against liability risk. Currently, physicians may be concerned that they could face a liability risk for investigational drugs that they recommend to patients or help them gain access to, potentially discouraging them from doing so. The FDA does not have jurisdiction over this issue but there is a bill in Congress, the Compassionate Access Act of 2010 (H.R. 4732), that would address the situation.[6][8][9]
  • Paying for the drug. While the FDA allows drug companies to recover the costs of providing a treatment through an EAP, many companies may hesitate to do so because it requires disclosing the cost of their drug, which is often a closely guarded secret. In addition, many insurance companies won’t cover the costs of experimental treatment so access could be limited to patients with the means to pay for it.[6][8]
  • Assessing the potential impact of adverse events on drug development. Adverse events (AEs) that result from expanded access programs must be reported to the FDA in the same way AEs are reported in the case of a clinical trial. The FDA states that, to their knowledge, no drug candidate has been turned down for approval because of an adverse event that appeared in an expanded access program.[3][6]

Outside the United States

Outside the U.S., programs that enable access to drugs in the pre-approval and pre-launch phase are referred to by a variety of names including “named patient programs,” “named patient supply” and “temporary authorization for use.”[10] In the EU, named patient programs also allow patients to access drugs in the time period between centralized European Medicines Agency (EMEA) approval and launch in their home countries which can range from one year to eighteen months.[11]

References

  1. Jump up^ US National Cancer Institute – Access to Investigational Drugs accessed April 22, 2007
  2. Jump up^ FDA Final Rules for Expanded Access to Investigational Drugs for Treatment Use and Charging for Investigational Drugs
  3. Jump up to:a b c d e f Final FDA Rules on Expanded Access to Investigational Drugs for Treatment Use
  4. Jump up to:a b FDA website
  5. Jump up^ Expanded Access to Investigational Drugs Genetic Engineering & Biotechnology News, January 15, 2010.
  6. Jump up to:a b c d e Access to Investigational Drugs Remains Challenge Despite New FDA Rules ‘’The Pink Sheet’’
  7. Jump up^ Managing Access to Drugs Prior to Approval and Launch ‘’Life Science Leader’’[dead link]
  8. Jump up to:a b c FDA webinar accessed May 5, 2010
  9. Jump up^ FDA Law Blog accessed May 5, 2010
  10. Jump up^ Helene S (2010). “EU Compassionate Use Programmes (CUPs): Regulatory Framework and Points to Consider before CUP Implementation”Pharm Med 24 (4): 223–229.
  11. Jump up^ [Ericson, M., Harrison, K., Laure, N. & De Crémiers, F., Compassionate Use Requirements in the Enlarged European Union. RAJ Pharma, May 2005: 83.

External links

 

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Aug 202014
 
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Sanofi and global health charity PATH have come together to launch a large-scale production line of malaria jab semisynthetic artemisinin at Sanofi’s Garessio site in Italy.

Global demand for artemisinin, the key ingredient of artemisinin-based combination therapies (ACTs) for malaria, has increased since the World Health Organization identified ACTs as the most effective malaria treatment available.

Because the existing botanical supply of artemisinin – derived from the sweet wormwood plant – is inconsistent, having multiple sources of high-quality product will strengthen its supply chain, contribute to a more stable price, and ultimately ensure greater availability of treatment to people suffering from malaria, according to Sanofi.

read at

http://www.pharmafile.com/news/192711/sanofi-and-path-launch-large-scale-malaria-drug-production

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Aug 182014
 

 

Antimicrobials are medicines that kill or inactivate microbes, small disease-causing organisms. They include antibiotics, which are used against bacteria. After being exposed to an antimicrobial repeatedly, microbes can undergo changes that stop them being killed or inactivated by the treatments. This is known as antimicrobial resistance.

The European Medicines Agency is concerned about the development of antimicrobial resistance, particularly resistance to antibiotics. A well-known example of a bacterium that is resistant to a number of antibiotics is meticillin-resistant Staphylococcus aureus(MRSA), which has caused infections that are difficult to treat across the European Union (EU).

 

This problem is being made worse by the fact that few new antimicrobials have been authorised over the past few years. This may lead to infections becoming more difficult to treat in the future.

Antimicrobial resistance is a growing problem in humans and in animals. Resistance can also spread from animals to humans through the food chain or direct contact.

The role of the Agency

The Agency works in collaboration with its EU and international partners in a number of initiatives aiming to limit the development of resistance. It is also monitoring and evaluating the risks to human and animal health.

A major such initiative is the Transatlantic Task Force on Antimicrobial ResistanceExternal link icon(TATFAR), which was established following the EU-United States summit in November 2009. The Task Force aims to increase levels of communication, coordination and co-operation between the EU and the United States on human and veterinary antimicrobials.

 

Human health

In human medicine, the availability of medicines to treat infections with resistant organisms has become a major problem in recent years.

In September 2009, the Agency published a joint report together with the European Centre for Disease Prevention and ControlExternal link icon (ECDC) and the international network ReAct – Action on Antibiotic ResistanceExternal link icon. This report highlights the gap between infections due to resistant bacteria and the development of new antibiotics.

The report states that at least 25,000 patients in the EU die each year from infections due to bacteria that are resistant to many medicines, and that infections due to these bacteria in the EU result in extra healthcare costs and productivity losses of at least €1.5 billion each year. Although it identified 15 antibiotics under development, most of these were early in development and were targeted against bacteria for which treatment options were already available.

 

Authorisation of new antibiotics

The Agency plays a key role in the authorisation of new antibiotics, because medicines with a significant therapeutic innovation or that are in the interest of public or animal health are authorised centrally in the EU, on the recommendation of the Agency.

In January 2012, the Agency updated its guidance to companies developing antibiotics, covering how they should carry out studies to test these medicines’ benefits and risks:

This is accompanied by an addendum giving information on how to study medicines for specific indications. The final addendum was published in November 2013 following a public consultation:

 

Animal health

The Agency is focused on promoting the prudent use of antimicrobials in animals, to limit the development of resistance. This goal is addressed in this document:

In line with this strategy, the Agency published a revised version of its guideline onefficacy for public consultation in May 2013. This draft guideline provides detailed recommendations for the design and conduct of pre-clinical and clinical studies to support clinical efficacy for antimicrobial veterinary products:

Since early 2010, the Agency has been leading a project collecting information on the sale of veterinary antimicrobials across the EU:

The CVMP has also published a large number of documents on microbial resistance in animals and its risks for humans.

Reports published by the Agency together with other European bodies, including ECDC, EFSA and the European Commission’s Scientific Committee on Emerging and Newly Identified Health RisksExternal link icon (SCENIHR) have emphasised the need for the prudent use of antibiotics in animals and the role of basic hygiene, and called for strengthened surveillance of resistance, the development of new antimicrobials and new strategies to combat the spread of resistance:

In 2013 and 2014, the Agency carried out a large body of work to provide advice to the European Commission on the use of antibiotics in animals and the impact on public health and animal health.

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Aug 182014
 

 

August 15, 2014

Release

Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.

Akman pleaded guilty in the U.S. District Court for the Eastern District of Missouri, in St. Louis, Missouri, where he initially shipped his illegal drugs. The drugs did not meet the FDA’s standards and had not been approved for distribution in the United States.

The FDA’s Office of Criminal Investigations coordinated a complex, multi-layered international investigation that led to Akman’s arrest in Puerto Rico in January 2014. The investigation identified Akman and his company as a source of Altuzan, the Turkish version of the cancer treatment drug Avastin.

“These criminals exploited our most vulnerable patients when they arranged for their illicit drugs to be brought into the United States and used to treat cancer patients. We will continue to investigate and bring to justice those who prey on our ill, susceptible patients,” said Philip J. Walsky, acting director of the FDA’s Office of Criminal Investigations. “We commend our colleagues – international, national, state, and local – whose contributions helped bring this case to a successful conclusion.”

Akman, along with his employee, Ozkan Semizoglu, obtained the illicit drugs and then used shipping labels to conceal the illegal nature of the shipments, including customs declarations falsely describing the contents as gifts. They also broke large drug shipments into several smaller packages to reduce the likelihood of seizures by U.S. Customs and Border Protection authorities.

Along with the FDA and Europol, the international operation involved several German government offices: the Bonn prosecutor; the Federal Criminal Police, the Dusseldorf police, and the German State Criminal Police.  Special agents of the U.S. Department of State’s Diplomatic Security Service assigned to the U.S. Embassy’s Regional Security Office in Ankara, Turkey, and the U.S. Consulate General’s Overseas Criminal Investigations Branch in Istanbul, Turkey also played key roles in the successful resolution of this case.

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Aug 182014
 

 

One of the European Medicines Agency’s long-term strategic goals is to foster researchand the uptake of innovative methods in the development of medicines.

READ………….Road map to 2015

The European Medicines Agency’s
contribution to science, medicines and health……………..http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101373.pdf

This helps the Agency to meet its objective of making safe and effective medicines available to patients in a timely manner, following evaluation using state-of-the-art methods.

The Agency also supports the development of new therapies and technologies by working with interested parties in the European Union (EU).

Activities at the Agency

In 2004, the Agency set up the European Medicines Agency/Committee for Medicinal Products for Human Use (CHMP) Think-Tank Group on Innovative Drug Development.

This group included Agency staff and members of the CHMP and its working parties. Its work focused on identifying scientific bottlenecks and emerging science in the development of medicines, both in industry research and development and in academia, and on generating recommendations for future activities at the Agency:

In 2008 the EMA and its Scientific Committees integrated the recommendations made by the Think Tank in its strategy for supporting innovative medicines developments. Key areas of action included the strengthening of the EU scientific network model, emphasis on communication during the lifecycle of medicinal products development and international activities. Overview of measures implemented in the period 2008-2010.

The recently published Road Map to 2015 further expands on the role the Agency plays to promote innovation in pharmaceuticals.

The Agency also contributes to the Innovative Medicines InitiativeExternal link icon (IMI). This is a public-private initiative that aims to speed up the development of better and safer medicines for patients:

Support for business

The Agency provides support for business on issues related to innovative medicines:

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Aug 182014
 

lupin ltd biosimilarnews Lupin launches insulin glargine in India

Lupin launches insulin glargine in India:

Indian pharma company, Lupin Limited announced a strategic distribution agreement with LG Life Sciences of South Korea to launch Insulin Glargine, a novel insulin analogue under the brand name Basugine™.

According to the agreement, Lupin would be responsible for marketing and sales of Basugine™ in India.

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http://www.biosimilarnews.com/lupin-launches-insulin-glargine-in-india?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=0b76af10ab-15_08_2014_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-0b76af10ab-335885197

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Aug 182014
 

 

Celltrion files Remsima in the United States:

Celltrion announced that the company, on August 8, 2014, completed the filing procedure to obtain US FDA approval for its infliximab biosimilar. This marks the first 351(k) biosimilar mAb application to be filed in the U.S.A. and the second application for a biosimilar to be filed through the US BPCIA.

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http://www.biosimilarnews.com/celltrion-files-remsima-in-the-us?utm_source=Biosimilar%20News%20%7C%20Newsletter&utm_campaign=0b76af10ab-15_08_2014_Biosimilar_News&utm_medium=email&utm_term=0_9887459b7e-0b76af10ab-335885197

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