Human immunodeficiency virus efavirenz

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

Martinez E, Arnaiz JA, Podzamczer D, Dalmau D, et al. 2003. Substitution of nevirapine, efavirenz or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. NEJM. 349 1036-1046. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

Mutlib AE, Chen H, Nemeth G, et al. Liquid chromatography/mass spectrometry and high-field nuclear magnetic resonance characterization of novel mixed diconjugates of the non-nucleoside human immunodeficiency virus-1 reverse transcriptase inhibitor, efavirenz. Drug Metab Dispos. 1999 27(9) 1045-1056. 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

Veldkamp AI, Harris M, Montaner JSG, Moyle G, Gazzard B, Youle M, Johnson M, Kwakkel-stein MO, Carlier H, van Leeuwen R, Beijnen JH, Lange JT Reiss P, Hoetelmans RMW. The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons. J InfectDis (2001) 184,37-42. 

Duval X, Le Moing V, Longuet P, Leport C, Vilde J L, Lamotte C, Peytavin G, Farinotti R. Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus-infected patients and correction hy ritonavir. Antimicrob Agents Cbemotber (2000) 44, 2593. 

Falloon J, Piscitelli S, Vogel S, Sadler B, Mitsuya H, KavUck MF, Yoshimura K, Rogers M, LaFon S, Manion DJ, Lane HC, Masur H. Comhination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV) infected patients failing a protease-inhibitor regimen pharmacokinetic drug interactions and antiviral activity. Clin bfect Dis (2000) 30, 313-18. 

Hsu A, Isaacson J, Brun S, Bernstein B, Lam W, Bertz R, Foit C, Rynkiewicz K, Richards B, King M, Rode R, Kempf DJ, Granneman GR, Sun E. Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Cbemotber (2003) 47, 350-9. 

Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Kumar P, Ramesh K, Anitha S, Narendran G, Menon P, Gomathi C, Swaminathan S. CYP2B6 G516T polymorphism but not rifampin coadministration influences steady-state pharmacokinetics of efavirenz in human immunodeficiency virus-infected patients in South India. Antimicrob Agents Che-mother 2009 53(3) 863-8. 

Biological target Efavirenz is a non-nucleoside analogue, direct inhibitor of reverse transcriptase (RT) and thus blocks the transcription of human immunodeficiency virus-1 (HIV-1) viral RNA into the genome of infected cells. The binding at the active site of RT involves unique steric interactions. 

Simon, VA. Thiam, M.D. Lipford, L.C. Determination of serum levels of thirteen human immunodeficiency virus-suppressing drugs by high-performance hquid chromatography, J.ChromatogrA, 2001,913,447-453. [zalcitabine lamivudine stavudine didanosine zidovudine nevirapine abacavir indinavir delavirdine nelfinavir saquinavir ritonavir efavirenz]... 

SPE LOD 260 ng/mL for lamivudine zalcitabine lamivudine stavudine didanosine zidovudine nevirapine abacavir indinavir deiavirdine nelimavir saquinavir ritonavir efavirenz] Solas, C. Li, Y.-F. Xie, M.-Y. Sommadossi, J.-P. Zhou, X.-J. Intracellular nucleotides of (-)-2, 3 -deoxy-3 -thiacytidine in peripheral blood mononuclear cells of a patient infected with human immunodeficiency virus, Aratimicro6..4 erats Chemother., 1998, 42, 2989-2995. 

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