Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/ zidovudine, and ethinyloestradiol/ levonorgestrel in healthy volunteers

Abel, Sylvie; Russell, D A; Whitlock, Lyndsey A.; Ridgway, Caroline; Muirhead, Gary J.

doi:10.1111/j.1365-2125.2008.03132.x

Cited by 53 publications

(43 citation statements)

References 22 publications

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“…Combining CCR5-antagonists with CNIs and mTOR inhibitors may improve both transplant outcomes and viral control in patients with CCR5 positive HIV, but cannot be applied in all HIV-infected patients because the use of MVC is limited to HIV strains using CCR5 coreceptor. Since MVC is a substrate of CYP3A, but not an inhibitor or inducer, it is not expected to have any relevant pharmacokinetic interactions with immunosuppressants 75 In contrast, it is yet to be determined whether the initiation of MVC in these immunocompromised patients will be limited by high rates of opportunistic infections.…”

Section: Ccr5-antagonistsmentioning

confidence: 91%

Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

Maarseveen

Rogers

Trofe‐Clark

et al. 2012

AIDS Patient Care and STDs

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Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.

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Section: Ccr5-antagonistsmentioning

confidence: 91%

Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

Maarseveen

Rogers

Trofe‐Clark

et al. 2012

AIDS Patient Care and STDs

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“…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).…”

mentioning

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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“…cotrimoxazole, tenofovir, nevirapine, ethinyl estradiol and levonorgestrel. These agents have been shown to have little to no effect on maraviroc plasma levels [46][47][48] . Drug interactions in antiretroviral salvage therapy are common and complex.…”

Section: Drug Interactionsmentioning

confidence: 98%

Developing clinical role of a CCR5 co-receptor antagonist in HIV-1 infection

Caldwell

Evans

2008

Expert Opinion on Pharmacotherapy

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Background : Maraviroc is the only approved CCR5 coreceptor antagonist on the market for treatment of HIV-1 infection. It uses a previously untargeted step in the HIV-1 replication cycle necessary for viral entry into the host cell. Objective : This review will describe and evaluate recent clinical literature regarding maraviroc, focusing on safety, efficacy, and mechanisms of treatment failure. Methods : A search of the primary literature and conference abstracts was conducted using the keywords CCR5 antagonist, maraviroc, and UK-427857. Resulting articles were then compiled and analyzed in this review. Conclusion : Maraviroc is a potent inhibitor of HIV-1 replication and contributes to effective viral suppression in combination with traditional antiretroviral medications. Due to its numerous drug interactions, potential for severe adverse events, and relative paucity of clinical data in longterm randomized, controlled trials, maraviroc should be one of the final agents utilized in salvage therapy in combination with other active antiretroviral agents.

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Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/ zidovudine, and ethinyloestradiol/ levonorgestrel in healthy volunteers

Cited by 53 publications

References 22 publications

Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

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

Developing clinical role of a CCR5 co-receptor antagonist in HIV-1 infection

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