Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir.

Abstract

BACKGROUND:

Boceprevir represents a new treatment option for hepatitis C (HCV)-infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs.

METHODS:

A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10-31, plus concomitant boceprevir on days 25-31.

RESULTS:

Boceprevir decreased the exposure of all PI/r, with area under the concentration-time curve [AUC] from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval [CI], .55-.78) for ATV/r; 0.66 (90% CI, .60-.72) for LPV/r, and 0.56 (90% CI, .51-.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUC(τ)) by 22%-36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUC(τ) was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events.

CONCLUSIONS:

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.

• Authors: Ellen G J Hulskotte, Hwa-Ping Feng, Fengjuan Xuan, Marga G J A van Zutven, Michelle A Treitel, Eric A Hughes, Edward O'Mara, Stephen P Youngberg, John A Wagner, Joan R Butterton
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 56 Issue 5 Pg. 718-26 (Mar 2013) ISSN: 1537-6591 [Electronic] United States
• PMID: 23155151 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• HIV Protease Inhibitors
• Oligopeptides
• Protease Inhibitors
• Pyridines
• Sulfonamides
• Lopinavir
• Atazanavir Sulfate
• N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
• Proline
• Ritonavir
• Darunavir

Topics

• Adult
• Anti-HIV Agents (pharmacokinetics)
• Area Under Curve
• Atazanavir Sulfate
• Darunavir
• Dose-Response Relationship, Drug
• Drug Interactions
• Female
• HIV Protease Inhibitors (pharmacokinetics)
• HIV-1 (drug effects)
• Hepacivirus (drug effects)
• Humans
• Lopinavir (pharmacokinetics)
• Male
• Middle Aged
• Oligopeptides (pharmacokinetics)
• Proline (analogs & derivatives, pharmacokinetics)
• Protease Inhibitors (pharmacokinetics)
• Pyridines (pharmacokinetics)
• Ritonavir (pharmacokinetics)
• Sulfonamides (pharmacokinetics)
• Young Adult