Pharmacokinetics of GW433908, a Prodrug of Amprenavir, in Healthy Male Volunteers

These two Phase I, open‐label, single‐dose, randomized, crossover studies in 40 healthy male subjects investigated the pharmacokinetic and safety profiles of various formulations of the amprenavir prodrug GW433908 in the presence and absence of food compared with amprenavir capsules. GW433908 is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, with improved solubility over the parent molecule and a potential for reduced pill burden on current dosing regimens. The calcium salt of the prodrug, GW433908G, was selected for further investigation, as it appeared to offer the greatest potential for the development of new drug formulations. In the fasting state, (1) GW433908G tablet and suspension were bioequivalent in terms of both AUC and Cmax' and (2) GW433908G tablet and suspension were bioequivalent to amprenavir capsules for AUC; however, Cmax was lower with GW433908G. After a high‐fat meal compared with fasting, (1) the bioavailability of GW433908G suspension was decreased by 20% and Cmax by 41%, and (2) for GW433908G tablets, there was no influence on AUC (12% lower Cmax). After a low‐fat meal compared with fasting, (1) there was bioequivalence for GW433908G tablets, but (2) bioavailability was decreased by 23% for amprenavir capsules (Cmax was also lower, by 46%). Overall, for GW433908G and amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C12). Whether administered as tablets or suspension, GW433908G pharmacokinetics was only slightly affected by food. GW433908G tablets were well tolerated and delivered plasma amprenavir concentrations equivalent to the recommended therapeutic amprenavir dose but with fewer tablets. The possibility of a lower pill burden offered by GW433908 may be of clinical benefit in the treatment of HIV infection.

[1]  Douglas A. Wolfe,et al.  Nonparametric Statistical Methods , 1973 .

[2]  B. Sadler,et al.  Single-Dose Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, in Subjects with Normal or Impaired Hepatic Function , 2000, Antimicrobial Agents and Chemotherapy.

[3]  G. McClelland,et al.  The Use of Pharmacoscintigraphy to Elucidate Food Effects Observed with a Novel Protease Inhibitor (Saquinavir) , 1998, Pharmaceutical Research.

[4]  E D Blair,et al.  Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors , 1995, Antimicrobial agents and chemotherapy.

[5]  B. Sadler,et al.  Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor, following Oral Administration of Single Doses to HIV-Infected Adults , 1999, Antimicrobial Agents and Chemotherapy.

[6]  M. Trautmann,et al.  Effects of standard breakfast on pharmacokinetics of oral zidovudine in patients with AIDS , 1993, Antimicrobial Agents and Chemotherapy.

[7]  E. Furfine,et al.  HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. , 2000, Antiviral research.

[8]  Eric Woolf,et al.  Single-Dose Pharmacokinetics of Indinavir and the Effect of Food , 1998, Antimicrobial Agents and Chemotherapy.

[9]  D Johnson,et al.  The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group. , 1999, AIDS.

[10]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. , 1997, JAMA.

[11]  R. Barbhaiya,et al.  Effect of Time of Food Administration on the Bioavailability of Didanosine From a Chewable Tablet Formulation , 1993, Journal of clinical pharmacology.

[12]  G G Koch,et al.  The use of non-parametric methods in the statistical analysis of the two-period change-over design. , 1972, Biometrics.

[13]  J. Rabkin,et al.  Adherence: a necessity for successful HIV combination therapy. , 1999, AIDS.

[14]  B. Sadler,et al.  In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. , 1996, Antiviral research.

[15]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. , 1998, JAMA.

[16]  S. Kaul,et al.  Effect of Food on the Bioavailability of Stavudine in Subjects with Human Immunodeficiency Virus Infection , 1998, Antimicrobial Agents and Chemotherapy.

[17]  Jon Brumbaugh,et al.  DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION , 2000 .

[18]  V L Yu,et al.  Determinants of compliance with antiretroviral therapy in patients with human immunodeficiency virus: prospective assessment with implications for enhancing compliance. , 1996, AIDS care.

[19]  P. Davey,et al.  Cost Effectiveness of Once‐Daily Oral Antimicrobial Therapy , 1992, Journal of clinical pharmacology.