Background:  PA-457 is the first in a new class of oral antiretrovirals called maturation inhibitors. Maturation inhibitors specifically block the conversion of the capsid precursor CA-SP1 (p25) to mature capsid protein (p24), resulting in defective core condensation and the release of non-infectious virus particles. PA-457 potently inhibits HIV-1 replication including strains resistant to approved drugs and is highly active in the SCID mouse model of HIV-1 infection. Pre-clinical studies showed PA-457 has a promising pharmacokinetic and safety profile in animals.

Methods:  This was a 10-day, multiple dose, double-blind, placebo-controlled, dose escalation study of PA-457 administered orally to 3 groups (6 active:2 placebo) of healthy, male subjects. The doses studied were 25, 50, and 100 mg administered once daily for 10 days. The primary endpoints were pharmacokinetics and safety.

Results:  All doses of PA-457 were safe and well tolerated.  The mean (SD) pharmacokinetic parameters are listed in the table below.

Conclusions:  Once-daily doses of as much as 100 mg of PA-457 for 10 days were safe and well tolerated. PA-457 was rapidly absorbed with very high plasma concentrations and a long half-life that resulted in approximately 3- to 5-fold accumulation of drug in the plasma. The target therapeutic concentration (i.e., protein binding adjusted IC₉₀ value) for PA-457 is a trough of ~2.3 μg/mL. These data suggest that therapeutic concentrations can be safely achieved with a single, oral daily doses as small as 25 mg, while multiples approaching 10-fold the target trough concentration were achieved safely with multiple daily doses of 100 mg.

Keywords: PA-457; Pharmacokinetics; Safety