Elsevier

Antiviral Research

Volume 79, Issue 3, September 2008, Pages 143-165
Antiviral Research

Review
A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations

https://doi.org/10.1016/j.antiviral.2008.05.001Get rights and content

Abstract

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely irrelevant, except for “advanced salvage” drugs such as enfuvirtide. In resource-poor settings cost is a huge factor that limits drug access, resulting in high rates of new infection and subsequent mortality. IP coverage, where granted, can keep access prices for essential ARVs higher than would otherwise be the case. Large, innovator companies have made drugs available at prices very close to the cost of manufacturing for “lowest income” countries. Generic providers in India and elsewhere provide the largest supply of drugs for the developing world. The recent issuance of Voluntary and Compulsory Licenses (VLs, CLs) through the World Trade Organization's TRIP (Treaty Respecting Intellectual Property) provisions arguably contribute to bringing down access prices. The utilization of improved science, pooled purchasing and intelligent procurement practices all definitely contribute to access. This work surveys the production processes for several critical ARVs. These are discussed in terms of scale up, raw material/intermediates and active pharmaceutical ingredient (API) costs. In some cases new routes to APIs or critical intermediates are needed. Based on potential new chemistries, there are significant opportunities to reduce cost for a number of critical ARVs.

Introduction

Although the death toll from HIV/AIDS over the last quarter century has reached many millions, AIDS has become a manageable chronic disease. An impressive range of compounds (exactly 25) have so far been approved for HIV/AIDS treatment (De Clercq, 2007). Combination therapy with three or more antiretrovirals (ARV) provides relief of symptomatic disease, with most patients achieving increased CD4 levels and undetectable viral load in circulating blood plasma. Significant progress has been made for increased access to ARVs, with over 2 million patients in developing countries receiving ARVs at this time (1Q2008). The fixed-dose combination (FDC) “triomune™” (AZT + 3TC + nevirapine) from Cipla presently sells for approximately $95–140 per patient year, and is the standard first-line FDC in many developing countries. The demonstrated clinical superiority of “Atripla®” (EFV + TDF + FTC) (De Clercq, 2006) and new WHO recommendations have created significant pressure to establish this as a new standard for first-line treatment. One of the major constraints for treatment access is cost. Approximately 65–90% of the cost of ARV therapy derives from the active pharmaceutical ingredient (API).

There is an urgent need to find cheaper alternatives for the production of critical ARVs. This paper discusses methods of producing the APIs efavirenz, emtricitabine, tenofovir disoproxil fumarate, abacavir, ritonavir, lopinavir and atazanavir. With increasing need for improved therapies, there is a strong economic interest in the production of these compounds. This paper describes the most useful commercial processes to produce these compounds. The present work is not exhaustive, but aims to analyze the present situation concerning production costs and favorable alternatives.

Previous reviews (for example, Izawa and Onishi, 2006, De Clercq, 2001, De Clercq, 2005, Painter et al., 2004, Rodriguez-Barrios and Gago, 2004, Stolk and Lüers, 2004, Peçanha et al., 2002, De Clercq, 1998, Flexner, 1998, Wlodawer and Vondrasek, 1998, Antunes, 1996) emphasized the synthesis of particular classes of compounds or disclosed the development of these APIs.

Section snippets

Background

API costs represent a substantial majority of the overall cost of a finished dosage form. The synthesis of an API usually requires several chemical processing steps in which new chemical bonds are formed and molecular complexity increases. API processes are normally carried out in solution, thereby limiting overall process efficiency. Formulation of APIs into a finished dosage form is usually a single process without a change in molecular complexity. Formulation processes typically utilize

Efavirenz

Efavirenz (EFV) was discovered at the Merck Research Laboratories and licensed to Dupont Pharmaceuticals. Dupont carried EFV through development and commercialization. It is marketed as Sustiva® (Bristol-Myers Squibb) and Stocrin® (Merck). Young et al. (1996) obtained the original patent on the synthesis and HIV RT inhibition properties of efavirenz (5). Other researchers have improved this process (Radesca et al., 1997, Patel et al., 1999a, Patel et al., 1999b, Patel et al., 2000). The initial

Tenofovir disoproxil fumarate (TDF)

Tenofovir disoproxil fumarate is an acyclic nucleotide inhibitor of HIV-1 reverse transcriptase (for review, see De Clercq and Holý, 2005). The first members of this series to be synthesized were PMPA, 9-[2-(phosphonomethoxypropyl) adenine] 12 (Arimilli et al., 1997, Tsai et al., 1995) and PMEA, 9-[2-(phosphonomethoxyethyl) adenine] 13 (Kim et al., 1990, Starrett et al., 1994). The efficacy of the (R)-enantiomer of PMPA against HIV-1 reverse transcriptase was published by Balzarini et al., 1993

Emtricitabine

Emtricitabine, FTC (Emtriva®) is an inhibitor of HIV-1 reverse transcriptase for once-daily antiretroviral therapy (Cahn, 2004, Anon., 2004). Emtricitabine is a fluorinated l-nucleoside (Pankiewicz, 2000, Wang et al., 1998) closely related in structure and synthesis to lamivudine, 3TC (Coates et al., 2001). The use of emtricitabine has been restricted to co-dosing with TDF (Truvada™). Schinazi et al. (1992) described (−) and (±)-cis-5-fluoro-1-1[2-hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine,

Abacavir

The Wellcome Research Group described the production of Abacavir in two patents (Daluge, 1991a, Daluge, 1991b). These processes were reviewed in Kleeman's Encyclopedia (Kleemann and Engel, 1999). Abacavir 27 is a cyclopropylamine derivative of carbovir 28.

Rac-cis-(+)-carbovir 28 (Vince and Hua, 1990) can be obtained from reacting rac-cis-4-(hydroxymethyl)cyclopentenylamine 29 and 2-amino-4,6-dichloropyrimidine 30 to give intermediate 31. This is followed by coupling with the diazonium salt of p

Ritonavir and lopinavir

Ritonavir (RTV, 41) and lopinavir (LPV, 42) are protease inhibitors that share the same hydroxyethylene dipeptide core 43 (Kempf et al., 1995).

Synthetic approaches to 41 and 42 by making peptide bonds are obviously practical. Sequential coupling of the amines of a pseudo-C2 symmetric core with activated ester “wings” suggests the option of a common intermediate to both RTV and LPV.

Different strategies in developing industrial routes to lopinavir and ritonavir deserve attention. Kaletra® is the

Atazanavir

Atazanavir (BMS-232632, 58) is an aza-peptide isostere first registered in the USA in 2005 (Robinson et al., 2000, Gong et al., 2000). Voluntary licenses from the innovator company Bristol–Myers Squibb have been granted for generic production of this drug in India.

Bristol–Myers Squibb (Xu et al., 2002) has published details of the process used for production. Boronic acid derivative 59 is submitted to the Suzuki–Miyaura coupling with 2-bromopyridine using Pd catalysis. The reaction product 60

Conclusion

From the literature it is very clear that there are several suitable (and simple) processes to produce APIs of the selected critical ARV drugs. In some cases new routes to some feedstocks are needed in order to drive cost reduction for access. There is significant scope to reduce the production costs of several critical APIs. Most importantly, Izawa and Onishi (2006) have recently disclosed some industrial process to manufacture the core of the HIV protease inhibitors.

Acknowledgements

Support from World Health Organization (WHO), The Brazilian National Research Council (CNPq), The Brazilian Ministry of Education (CAPES) and The Rio de Janeiro Research Foundation (FAPERJ) is gratefully acknowledged. We are also grateful to Amolo Okero (WHO) for her contribution in organizing the final manuscript and to Jos Perriens (WHO) for substantial review and input towards the completion of the paper. The Clinton HIV/AIDS Initiative provided valuable data on the number of patients on

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