Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

Abstract

Current guidelines recommend the use of at least two, and preferably three, fully active antiretroviral agents in an optimized regimen for the treatment of HIV infection in treatment-experienced patients (13,21). Therefore, it is important to study and understand drug-drug interactions between different antiretrovirals, because these can impact individual pharmacokinetic profiles and lead to suboptimal responses and/or increased toxicities (5).Maraviroc is the first in a novel class of entry inhibitors, the chemokine C-C motif receptor 5 (CCR5) antagonists, and has demonstrated benefits for both treatment-naïve and treatment-experienced patients infected with CCR5-tropic HIV (11,14). Darunavir, in combination with low-dose ritonavir (darunavir-ritonavir), is an HIV protease inhibitor (PI) with demonstrated benefits for both treatment-naïve and treatment-experienced patients (10,17,19). Etravirine is an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) with a high genetic barrier to the development of resistance, in contrast to the NNRTIs efavirenz and nevirapine, and shows potent activity against NNRTI-resistant viruses. The efficacy and safety of etravirine for treatment-experienced patients were demonstrated in the phase III DUET trials (15,16,18).Since maraviroc is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (6), and since darunavir-ritonavir and etravirine inhibit and induce CYP3A, respectively, and both inhibit P-glycoprotein (8,20), there is a likelihood of drug-drug interactions between these agents. For example, most HIV PIs (either with or without low-dose ritonavir) increase maraviroc exposure, necessitating a reduction of the maraviroc dose to 150 mg twice daily (b.i.d.) (6).This article reports the results from two separate drug-drug interaction studies with healthy volunteers: (i) the effect of darunavir-ritonavir on the pharmacokinetics of maraviroc, and vice versa (darunavir-ritonavir study), and (ii) the effect of etravirine, alone or in combination with darunavir-ritonavir, on the pharmacokinetics of maraviroc, and vice versa (etravirine study).The primary objectives of the studies were to investigate the effect of darunavir-ritonavir at 600 and 100 mg b.i. was the highest dose being studied in phase III studies at the time and was therefore selected for coadministration with etravirine alone; 150 mg of maraviroc b.i.d. was selected for coadministration with etravirine-darunavir-ritonavir based on the results of the darunavir-ritonavir study (2). The results should provide appropriate dose recommendations for maraviroc when it is coadministered with these drugs in clinical practice.

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

“…Maraviroc was approved based on the MOTIVATE trials comprised of 85% individuals with European ancestry (Gulick et al, 2008) and most previous maraviroc pharmacokinetic studies were conducted in participants with European ancestry, with the median percentage of participants with European ancestry at 78.5% (Abel et al, 2008a,b,c,d,f;Chan et al, 2008;Pozniak et al, 2008;Dumond et al, 2009;Andrews et al, 2010;Ramanathan et al, 2010;Brown et al, 2011;Kakuda et al, 2011;Gruber et al, 2013;Mora-Peris et al, 2013;Taiwo et al, 2013;Vourvahis et al, 2013). A few studies compared maraviroc concentrations in individuals with African ancestry with individuals with European ancestry and concluded that there were no differences or higher concentrations in individuals with African ancestry (FDA, 2007;Okoli et al, 2012), which may be due to the use of CYP3A inhibitors such as ritonavir in the optimized background therapy in which CYP3A5 activity may have been inhibited in individuals who are carrying CYP3A5*1 allele.…”

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

“…ETR has been shown to decrease the exposure to maraviroc, an antiretroviral that is a substrate of CYP3A4 (Kakuda et al, 2011), in human subjects; however, the mechanism(s) underlying this are currently unknown. Experiments were therefore performed to determine whether ETR modulates the mRNA levels of CYP3A4 using primary human hepatocytes from four donors.…”

“…Because ETR is always taken concurrently with other antiretrovirals that are substrates, inhibitors, and inducers of drug-metabolizing enzymes (Kakuda et al, 2010;Calcagno et al, 2011), gaining a comprehensive understanding of the metabolic pathways involved in the clearance of ETR is important to minimize drug-drug interactions and adverse events. For instance, it has recently been demonstrated in healthy adults that ETR decreases exposure to certain antiretrovirals prescribed for the treatment of HIV including dolutegravir (by 70%) (Song et al, 2011) and maraviroc (by 53%) (Kakuda et al, 2011). CYP3A4 has been shown to play a central role in the N-dealkylation of maraviroc, which is the major route of maraviroc metabolism, raising the possibility that ETR decreases exposure to maraviroc in vivo via modulation of CYP3A4 expression and/or activity (Hyland et al, 2008).…”

Maraviroc in Antiretroviral-Naïve HIV-1 Patients

“…In a supportive study, the viral activity was studied in patients with non-CCR5-tropic virus. 34,35,[46][47][48] …”