Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers

Abel, Sylvie; Ryst, Elna van der; Rosario, M.; Ridgway, Caroline; Medhurst, Christine G; Taylor-Worth, Richard J; Muirhead, Gary J.

doi:10.1111/j.1365-2125.2008.03130.x

Cited by 80 publications

(77 citation statements)

References 15 publications

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“…Maraviroc exhibits near-dose-proportional pharmacokinetics at 300 mg b.i.d. (7). Consequently, for coadministration of maraviroc with CYP3A inducers such as efavirenz or etravirine, it is recommended to increase the maraviroc dose to 600 mg b.i.d.…”

Section: Discussionmentioning

confidence: 99%

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

Kakuda¹,

Abel

Davis

et al. 2011

Antimicrob Agents Chemother

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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.

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Section: Discussionmentioning

confidence: 99%

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

Kakuda¹,

Abel

Davis

et al. 2011

Antimicrob Agents Chemother

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“…It is known that maraviroc plasma concentration and exposure are significantly changed when coadministered with CYP3A inducers or inhibitors (Abel et al, 2008b;Boffito and Abel, 2008). The M1 formation activity of CYP3A5 exhibited an evident difference from that of CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 3A5 Plays a Prominent Role in the Oxidative Metabolism of the Anti-Human Immunodeficiency Virus Drug Maraviroc

Hendrix

Bumpus

2012

Drug Metab Dispos

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ABSTRACT:Maraviroc is an anti-human immunodeficiency virus drug that acts by blocking viral entry into target cells. With use of ultra-performance liquid chromatography-mass spectrometry several monooxygenated, dioxygenated, and glucuronidated metabolites of maraviroc were identified both in vitro and in vivo. Characterization of the enzymes involved in the production of these metabolites determined that cytochrome P450 3A5 was the principal enzyme responsible for the formation of an abundant metabolite of maraviroc that resulted from oxygenation of the dichlorocyclohexane ring. For the formation of this metabolite, the V max values for CYP3A4 and CYP3A5 were 0.04 and 0.93 pmol ⅐ min ؊1 ⅐ pmol P450 ؊1, and the K m values were 11.1 and 48.9 M, respectively. Furthermore, human liver microsomes isolated from donors homozygous for the loss-of-function CYP3A5*3 allele exhibited a 79% decrease in formation of this metabolite compared with those homozygous for the wild-type CYP3A5*1 allele. To probe which divergent residues between CYP3A4 and CYP3A5 might play a role in the differential activities of these enzymes toward maraviroc, mutations were introduced into both enzymes and metabolism of maraviroc was measured. A CYP3A5 L57F mutant exhibited a 61% decrease in the formation of this metabolite, whereas formation by a CYP3A4 F57L mutant was increased by 337% compared with that of the wild type. Taken together, these data provide novel insights into the biotransformation of maraviroc as well as the potential role of CYP3A4 and CYP3A5 divergent residues in the enzymatic activities of these two highly homologous enzymes.

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“…However, there were no significant differences seen in grade 3 or 4 abnormalities [89][90][91], and whether this is an immune-mediated phenomenon is unknown. Hepatotoxicity, seen with the discontinued CCR5 co-receptor antagonist aplaviroc, does not appear to be a class effect [92].…”

Section: Entry Inhibitors (Ei)-fusion Inhibitors and Ccr5 Inhibitorsmentioning

confidence: 91%

Hypersensitivity reactions to HIV therapy

Chaponda

Pirmohamed

2011

Brit J Clinical Pharma

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Many drugs used for the treatment of HIV disease (including the associated opportunistic infections) can cause drug hypersensitivity reactions, which vary in severity, clinical manifestations and frequency. These reactions are not only seen with the older compounds, but also with the newer more recently introduced drugs. The pathogenesis is unclear in most cases, but there is increasing evidence to support that many of these are mediated through a combination of immunologic and genetic factors through the major histocompatibility complex (MHC). Genetic predisposition to the occurrence of these allergic reactions has been shown for some of the drugs, notably abacavir hypersensitivity which is strongly associated with the class I MHC allele, HLA-B*5701. Testing before the prescription of abacavir has been shown to be of clinical utility, has resulted in a change in the drug label, is now recommended in clinical guidelines and is practiced in most Western countries. For most other drugs, however, there are no good methods of prevention, and clinical monitoring with appropriate (usually supportive and symptomatic) treatment is required. There is a need to undertake further research in this area to increase our understanding of the mechanisms, which may lead to better preventive strategies through the development of predictive genetic biomarkers or through guiding the design of drugs less likely to cause these types of adverse drug reactions.

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Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers

Cited by 80 publications

References 15 publications

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

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

Cytochrome P450 3A5 Plays a Prominent Role in the Oxidative Metabolism of the Anti-Human Immunodeficiency Virus Drug Maraviroc

Hypersensitivity reactions to HIV therapy

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