Safety, pharmacokinetics, and antiviral activity of A77003, a C2 symmetry-based human immunodeficiency virus protease inhibitor

Abstract

A77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, was administered to asymptomatic HIV-1-infected patients in a phase I trial. The drug was given by continuous intravenous infusion at dosages of 0.035, 0.07, 0.14, and 0.28 mg/kg of body weight per h. The drug was given first for 24 h and then for up to an additional 4 weeks in a second infusion period following at least a 6-day washout. Apart from reversible increases in hepatic transaminase levels in some patients, no systemic toxicities occurred during extended infusion of the drug. Dose-related local vein irritation, despite dilution of the infusate, however, caused severe infusion site phlebitis precluding dosage escalation beyond 0.28 mg/kg/h. Pharmacokinetic analysis demonstrated dose linear increases in mean steady-state concentrations. However, clearance of the drug from plasma was unexpectedly high, averaging 62 liters/h across all groups. The concentrations of A77003 in plasma achieved the in vitro 50% inhibitory concentration (0.16 g/ml) only in the 0.28-mg/kg/h dosage group, but it did not attain the 90% inhibitory concentration (0.48 g/ml). No statistically significant effect on CD4 cell numbers occurred in any of the groups, and there was no evidence of antiviral activity, as determined by HIV-1 p24 antigen level, quantitative plasma and cell culture, and quantitation of viral RNA in plasma. In conclusion, A77003, as formulated in the present study, causes severe phlebitis, which prevents administration of the infusates necessary to achieve high concentrations of the drug in plasma. The lack of antiviral activity observed in the study may be a consequence of the low concentrations in plasma in all groups.

Human serum alpha 1 acid glycoprotein reduces uptake, intracellular concentration, and antiviral activity of A-80987, an inhibitor of the human immunodeficiency virus type 1 protease

“…One scenario in which protein binding may potentiate activity in vivo is if ␣ 1 AGP binding leads to increased tissue penetration and/or reduced clearance. A77003, a closely structurally related, highly protein-bound protease inhibitor, was studied in humans in a phase I͞II clinical trial (28). The fact that A77003 was extensively protein bound would have led one to believe that clearance rate for this drug would be quite low.…”

A Short-Term Study of the Safety, Pharmacokinetics, and Efficacy of Ritonavir, an Inhibitor of HIV-1 Protease

“…The large size of many of these agents makes their absorption difficult, and they may be rapidly cleared from plasma, as has been noted with two of the first protease inhibitors studied in humans, A-77003 and saquinavir. 4,5 Ritonavir is a novel inhibitor of HIV-1 protease that has good oral bioavailability in dogs and monkeys (90 and 70 percent, respectively; unpublished data). It has potent antiretroviral activity and reached high plasma concentrations safely in phase 1 clinical trials.…”

Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation

“…The values of the pharmacokinetic parameters for the simulations were drawn from the report of Gitterman et al (12) for zidovudine. For A-77003, the values of the pharmacokinetic parameters were taken from the report of Reedjik et al (17). Simulations were accomplished with the ADAPT II package of programs of D'Argenio and Schumitzky (9).…”

“…Indeed, an underlying assumption in the present evaluation is that there would be the same response at each dosing interval (i.e., no emergence of resistance). Some idea of the correctness of the evaluation presented here can be obtained by examining the phase I evaluation of A-77003 (17) and the time course of efflux of a closely related protease inhibitor, A-80987, from HIV-infected cells (the only radiolabelled inhibitor available to us) from HIV-infected cells. Once the drug is removed from the area outside of the cell and the gradient is maximized, the efflux of A-80987 from the cell is remarkedly rapid, with a half-time on the order of 8 min (Fig.…”