Pharmacokinetic effects of coadministration of lersivirine with raltegravir or maraviroc in healthy subjects.

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.
AuthorsManoli Vourvahis, Grant Langdon, Robert R Labadie, Gary Layton, Marie-Noella Ndongo, Subhashis Banerjee, John Davis
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 2 Pg. 887-92 (Feb 2012) ISSN: 1098-6596 [Electronic] United States
PMID22123705 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-HIV Agents
  • Cyclohexanes
  • HIV Fusion Inhibitors
  • HIV Integrase Inhibitors
  • Nitriles
  • Pyrazoles
  • Pyrrolidinones
  • Reverse Transcriptase Inhibitors
  • Triazoles
  • UK 453,061
  • Raltegravir Potassium
  • maraviroc
  • Adolescent
  • Adult
  • Anti-HIV Agents (administration & dosage, pharmacokinetics)
  • Cross-Over Studies
  • Cyclohexanes (administration & dosage, pharmacokinetics)
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • HIV Fusion Inhibitors (administration & dosage, pharmacokinetics)
  • HIV Integrase Inhibitors (administration & dosage, pharmacokinetics)
  • Humans
  • Male
  • Middle Aged
  • Nitriles (administration & dosage, pharmacokinetics)
  • Pyrazoles (administration & dosage, pharmacokinetics)
  • Pyrrolidinones (administration & dosage, pharmacokinetics)
  • Raltegravir Potassium
  • Reverse Transcriptase Inhibitors (administration & dosage, pharmacokinetics)
  • Treatment Outcome
  • Triazoles (administration & dosage, pharmacokinetics)
  • Young Adult

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