Role of Ritonavir in the Drug Interactions Between Telaprevir and Ritonavir-Boosted Atazanavir

• Published in: Clinical infectious diseases 2014-01, Vol.58 (2), p.268-273
• Main Authors: Gutierrez-Valencia, Alicia, Ruiz-Valderas, Rosa, Torres-Cornejo, Almudena, Viciana, Pompeyo, Espinosa, Nuria, Castillo-Ferrando, Juan R., Lopez-Cortes, Luis F.
• Format: Article
• Language: English
• Subjects: Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiviral agents; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Atazanavir Sulfate; Biological and medical sciences; Chromatography; Chromatography, Liquid; Confidence intervals; Drug Interactions; Drug Therapy, Combination - methods; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - drug therapy; HIV; HIV Infections - complications; HIV Infections - drug therapy; HIV/AIDS; Human immunodeficiency virus; Humans; Infectious diseases; Interferon-alpha - therapeutic use; Male; Mass Spectrometry; Medical sciences; Middle Aged; Oligopeptides - pharmacokinetics; Oligopeptides - therapeutic use; Pharmacology; Pharmacology. Drug treatments; Plasma - chemistry; Protease inhibitors; Pyridines - pharmacokinetics; Pyridines - therapeutic use; Ribavirin - therapeutic use; Ritonavir - pharmacokinetics; Ritonavir - therapeutic use; Switching
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/cit693

Ritonavir (RTV) is responsible for the adverse interactions that occur when telaprevir and RTV-boosted atazanavir are administered together. The coadministration of telaprevir and unboosted atazanavir results in increased exposure of both drugs compared with their coadministration with RTV. Background.  Detrimental bidirectional pharmacokinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immunodeficiency virus (HIV) protease inhibitors are coadministered in healthy volunteers. Our aim was to evaluate the role of RTV in the bidirectional TVR and atazanavir (ATV) interactions. Method.  An open-label, sequential study was carried out in hepatitis C virus (HCV)/HIV–coinfected patients on a RTV-boosted ATV-based (ATVr) antiretroviral regimen (300/100 mg every 24 hours) and triple therapy for chronic C hepatitis genotype 1 (TVR, 1125 mg every 12 hours, pegylated interferon-alpha and ribavirin). Pharmacokinetic profiles were acquired before and after switching from ATVr to unboosted ATV (200 mg every 12 hours). The plasma levels of both drugs were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis and compared by geometric mean ratios and their 90% confidence intervals. Results.  Fourteen white HCV/HIV–coinfected males were enrolled in this study. After RTV was withdrawn, the TVR AUC0–12 (area under the concentration–time curve), maximum concentration (Cmax), and minimum concentration (Cmin) values increased by 19% (7%–30%), 12% (0.9%–29%), and 18% (2%–34%), respectively, without any changes in the TVR terminal half-life. The ATV AUC0–12, Cmax, and Cmin values were 39% (13%–66%), 19% (8%–59%), and 48% (1%–96%) higher, respectively, with a significantly shorter terminal half-life (22.6 hours vs 10.4 hours). Conclusions.  RTV is responsible for the adverse interactions that occur when TVR and ATVr are administered together, possibly by influencing either the absorption phase or first-pass metabolism of TVR. The boost effect of TVR on ATV exposure is higher than on RTV, despite its shorter terminal half-life. The coadministration of TVR and unboosted ATV results in increased exposure of both drugs compared with their coadministration with RTV. Clinical Trials Registration.  ClinicalTrials.gov: NCT01818856. European Medicines Agency EudraCT no. 2012-002515-25.