Lersivirine (UK-453,061) is a new nonnucleoside
reverse transcriptase inhibitor currently being developed as a treatment for human immunodeficiency virus type 1
infection.
Lersivirine shows potent activity against wild-type and clinically relevant
drug-resistant strains. Previous studies have demonstrated that
lersivirine is metabolized by glucuronidation via UGT2B7 and by
cytochrome P450 3A4 (
CYP3A4).
Lersivirine is also a weak inducer of the
CYP3A4 enzyme. Therefore, coadministered
lersivirine could potentially affect the pharmacokinetics of
maraviroc, a CCR5 antagonist metabolized by
CYP3A4, and
raltegravir, an
integrase inhibitor metabolized by glucuronidation. Two open-label studies assessed the pharmacokinetics of
raltegravir and of
maraviroc when they were coadministered with
lersivirine and the pharmacokinetics of
lersivirine when it was coadministered with
raltegravir. Minor, clinically nonsignificant effects on the pharmacokinetics of
raltegravir coadministered with
lersivirine were observed at steady state for
raltegravir, with estimated mean changes of -15%, -29%, and +25% in the area under the concentration-time profile from time zero to the end of the dosing interval (AUC(tau)), maximum plasma concentration (C(max)), and concentration observed 12 h postdose (C(12)), respectively. There were no clinically relevant effects of steady-state
raltegravir on
lersivirine AUC(tau), C(max), or concentration observed 24 h postdose (C(24)) (estimated mean changes of -2 to +5%). Coadministration of
lersivirine at steady state with
maraviroc resulted in no clinically relevant effects on
maraviroc AUC(tau), C(max), or C(12) (estimated mean changes of +3.4 to +8.6%).
Lersivirine appeared to be generally well tolerated in these studies and appears to be suitable for coadministration with
raltegravir or
maraviroc without the need for dose modification.