necessitates the continued development of novel antiretroviral agents . Lersivirine is an investigational NNRTI with a unique binding interaction within the NNRTI binding pocket . Lersivirine has in vitro antiretroviral activity against Abiraterone wild type virus as well as clinically relevant NNRTI resistant strains, luding viruses with transmitted resistance to NNRTI . In HIV 1 infected NNRTI naïve subjects, treatment with lersivirine monotherapy for 7 days achieved mean viral RNA reductions of 1.7 log10 copies/ml and 1.8 log10 copies/ml after administration of 500 and 750 mg once daily , respectively, and 1.6 log10 copies/ml after administration of 500 mg twice daily . Lersivirine was generally safe and well tolerated, with the most commonly reported treatment emergent adverse events being headache, fatigue, and nausea .
Synergy between lersivirine and other classes of compounds, most notably the NRTI class, has been demonstrated in vitro . Lersivirine has been assessed at doses up to 1,800 mg QD and is currently undergoing phase IIb studies in combination Adrenergic Receptors with tenofovir and emtricitabine in treatment naive patients with HIV and in combination with darunavir and ritonavir plus an optimized NRTI in treatment experienced patients with HIV . Data from an in vivo mass balance study and in vitro metabolism studies suggest that lersivirine is predominantly cleared by metabolism, with glucuronidation and oxidation via cytochrome P450 3A4 being the major metabolic pathways . Recombinant CYP3A4 metabolizes lersivirine, with an intrinsic clearance rate of 0.9 l/pmol CYP/min .
anthropology The only other enzyme shown to metabolize lersivirine based upon a substrate depletion approach was CYP3A5, with a rate of metabolism more than 10 fold lower than that of CYP3A4 . Lersivirine is a weak inducer of CYP3A4 and, based on in vitro data, is an inhibitor and substrate for P glycoprotein . activity of important drug metabolizing enzymes and transporters, such as CYP3A4 and P gp . Because patients are likely to receive treatment for life and because of the possibility of potential drug interactions, rigorous pharmacokinetic investigation is a requisite step in the development of new HIV drugs, both to determine their suitability for introduction into existing treatment regimens and to define dose adjustments, if necessary.
Here we report the results from two open label studies designed to assess the pharmacokinetics of raltegravir and maraviroc, both first in class agents, when they are coadministered with lersivirine and the pharmacokinetics of lersivirine when it is coadministered with raltegravir. Raltegravir is an HIV 1 integrase inhibitor that is metabolized predominantly through UGT1A1 mediated glucuronidation . Maraviroc is a CCR5 antagonist that is a substrate for both CYP3A4 and P gp . MATERIALS AND METHODS Two phase I clinical trials investigating the pharmacokinetics of coadministration of lersivirine with raltegravir and maraviroc were performed. Study 1 was conducted at the Pfizer Clinical Research Unit in New Haven, CT, and study 2 was conducted at the Pfizer CRU in Brussels, Belgium. All protocols were approved by the Institutional Review Board of the investigational centers and were conducted in accordance with the ethical priples established .