Drug Interactions with New and Investigational Antiretrovirals

iThe objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV ؉ ) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare onceand twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV ؉ than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Section: Discussionsupporting

confidence: 76%

“…Plasma concentrations ranged between 4 and 10,192 ng/ml. Demographic characteristics of the HIV ϩ population are summarized in Table 1, and the description of the population of healthy volunteers (HIV Ϫ ) is as reported by Neely et al (7,29). First, the analysis of HIV Ϫ rich data was performed.…”

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir in HIV-Positive and Healthy Individuals

Arab‐Alameddine

Fayet-Mello

Lubomirov

et al. 2012

“…Evidence from clinical trials suggests that etravirine is less prone to drug-drug interactions than other NNRTIs (4,15). Nevertheless, many drug-drug interactions have been described for this NNRTI, and for some interactions the mechanism is not clear.…”

mentioning

confidence: 99%

Interaction Potential of Etravirine with Drug Transporters Assessed In Vitro

Zembruski

Haefeli

Weiß

2011

Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infections. ABC transporters potentially mediate clinically relevant drug-drug interactions. We assessed substrate characteristics and the inhibitory and inductive potential of etravirine on ABC transporters. Etravirine did not inhibit P-gp/ABCB1 and was not transported by the tested ABC transporters but was a potent inhibitor of BCRP/ABCG2. Etravirine induced several ABC transporters, especially BCRP/ABCG2. These data demonstrate that etravirine has the potential for drug-drug interactions by modulation of expression and function of several ABC transporters.Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infections. It is active against wild-type and some NNRTI-resistant HIV strains (1, 2) and offers a new treatment option for treatmentexperienced patients. Pharmacokinetic drug-drug interactions considerably influence efficacy and safety of antiretroviral therapy. Interactions might lower concentrations of antiretrovirals below therapeutic concentrations (5,12,14) and cause treatment failure and viral resistance. Interactions may also increase drug exposure and augment toxicity.The main mechanisms of interaction in antiretroviral combination therapy involve the drug-metabolizing cytochrome P450 enzymes (CYPs) as well as efflux and uptake transporters. Crucial efflux transporters are several ATP-binding cassette (ABC) transporters that have been identified as important interaction sites of antiretroviral drugs (9-11). Relevant uptake transporters are the organic anion-transporting polypeptides (OATPs/SLCOs) (6,16,20). Information on interactions of etravirine is sparse. We therefore investigated whether etravirine is a substrate of P-gp/ABCB1, BCRP/ABCG2, MRP1/ ABCC1, MRP2/ABCC2, or MRP3/ABCC3 and whether it inhibits P-gp/ABCB1 and BCRP/ABCG2. Furthermore, we investigated etravirine's potency to induce ABC transporters, important OATPs/SLCOs, CYPs, and the transcription factor pregnane X receptor.Etravirine was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, as etravirine TMC125 (catalog no. 11609) from Tibotec, Inc. Other materials were used as described previously (13). Etravirine was tested for cytotoxic effects prior to P-gp/ABCB1 and BCRP/ABCG2 inhibition assays with a cytotoxicity detection kit (Roche Applied Science, Mannheim, Germany) according to manufacturer's instructions. Cytotoxic concentrations were excluded in the respective assays. P-gp/ABCB1 and BCRP/ABCG2 inhibition was quantified by calcein and pheophorbide A efflux assays as described previously (23, 26). We used the growth inhibition assay in MDCKII cells overexpressing human P-gp/ABCB1 (7), BCRP/ABCG2 (17), and MRP1-3/ABCC1-3 (8) as a surrogate for substrate characteristics of etravirine as it has been described for other antiretroviral drugs (3,13,26). The induction assay, quantification of mRNA expression by real-time reverse transc...

“…Lersivirine and maraviroc PK samples were collected into lithium heparin and raltegravir PK samples into dipotassium EDTA. The dose was to be increased on days 11 to 14 if a Ն25% difference was observed between placebo-adjusted comparison of day 1 and day 7 maraviroc C av (2)(3)(4) . BID, twice daily; C av (2)(3)(4) , geometric mean of the observed concentrations at 2, 3, and 4 h post dose; QD, once daily.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Effects of Coadministration of Lersivirine with Raltegravir or Maraviroc in Healthy Subjects

Vourvahis

Langdon

LaBadie

et al. 2012

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 drugresistant 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.