Pharmacokinetic Interactions Between the Hepatitis C Virus Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Darunavir, and Lopinavir

Hulskotte, Ellen; Feng, Hwa‐Ping; Xuan, Fengjuan; Zutven, M. G. J. A. van; Treitel, Michelle; Hughes, Eric; O’Mara, Edward; Youngberg, Stephen P.; Wagner, John A.; Butterton, Joan R.

doi:10.1093/cid/cis968

Cited by 77 publications

(56 citation statements)

References 17 publications

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“…Recently, drug interactions between BOC and several ritonavirboosted HIV protease inhibitors (atazanavir, lopinavir, darunavir) have been reported (Hulskotte et al, 2012a). Unexpectedly, the exposure of all agents (BOC, HIV agents, and ritonavir) was decreased.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldoketoreductases, was a reversible time-dependent inhibitor (k inact = 0.12 minute 21, K I = 6.1 mM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC 50 of 18 and 4.9 mM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.

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Section: Discussionmentioning

confidence: 99%

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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“…Therefore, telaprevir should not be coadministered with ritonavir-boosted darunavir, fosamprenavir, or lopinavir, 92 and boceprevir is not recommended for use with any boosted protease inhibitor. 93 Concentrations of boceprevir are significantly reduced in the presence of efavirenz, and this combination should be avoided. 94 Similarly, telaprevir concentrations are reduced by concomitant efavirenz; the possibility of using higher telaprevir doses to overcome this interaction is being explored.…”

Section: Hepatitis Cmentioning

confidence: 99%

Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines

Tseng

Foisy

Hughes

et al. 2012

CJHP

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“…The protease inhibitor BOC decreased the exposure of all protease inhibitors; ATV/ritonavir did not significantly affect BOC exposure, whereas BOC was reduced by 45% and 32% when co-administered with LPV/ritonavir and DRV/ritonavir, respectively [75] . In a recent study no significant drug interaction between BOC and raltegravir was found in healthy volunteers [76] .…”

Section: Art Management In Hiv/hcv Coinfected Patients During Treatmementioning

confidence: 85%

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

Coppola

Martini

Pisaturo

et al. 2015

WJV

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frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCVgenotype 1, both for the HCV-monoinfected and HIV/ HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/ 4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.

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Pharmacokinetic Interactions Between the Hepatitis C Virus Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Darunavir, and Lopinavir

Abstract: Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug-drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered.

Cited by 77 publications

References 17 publications

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

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