Effect of Low-Dose Omeprazole (20 mg Daily) on the Pharmacokinetics of Multiple-Dose Atazanavir With Ritonavir in Healthy Subjects

• Published in: Journal of clinical pharmacology 2011-03, Vol.51 (3), p.368-377
• Main Authors: Zhu, Li, Persson, Anna, Mahnke, Lisa, Eley, Timothy, Li, Tong, Xu, Xiaohui, Agarwala, Sangeeta, Dragone, Jeffrey, Bertz, Richard
• Format: Article
• Language: English
• Subjects: Adult; Antiretroviral drugs; Antiretroviral Therapy, Highly Active - methods; Area Under Curve; Atazanavir; Atazanavir Sulfate; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; drug-drug interactions; Female; HIV; HIV Infections - drug therapy; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - adverse effects; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacokinetics; Human immunodeficiency virus; Humans; Male; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Oligopeptides - blood; Oligopeptides - pharmacokinetics; omeprazole; Omeprazole - administration & dosage; Omeprazole - adverse effects; Omeprazole - pharmacokinetics; Omeprazole - pharmacology; pharmacokinetics; Proton Pump Inhibitors - administration & dosage; Proton Pump Inhibitors - adverse effects; Proton Pump Inhibitors - pharmacokinetics; Proton Pump Inhibitors - pharmacology; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - blood; Pyridines - pharmacokinetics; Ritonavir - administration & dosage; Ritonavir - adverse effects; Ritonavir - blood; Ritonavir - pharmacokinetics
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270010367651

Atazanavir, a potent protease inhibitor of human immunodeficiency virus (HIV), exhibits pH‐dependent solubility. Previous studies have indicated that coadministration with omeprazole 40 mg once daily significantly decreased atazanavir exposure by approximately 75%. Concomitant use of omeprazole and atazanavir is currently not recommended. This study investigated a clinically effective, low dose of omeprazole (20 mg daily) on atazanavir pharmacokinetics in 56 healthy volunteers given atazanavir/ritonavir 300/100 and 400/100 mg once daily. All atazanavir/ritonavir plus omeprazole combinations resulted in atazanavir area under the concentration‐time curve (AUC) and trough concentrations (Cmin) comparable to or exceeding those observed with atazanavir 400 mg without omeprazole. Compared with atazanavir/ritonavir 300/100 mg without omeprazole, atazanavir/ritonavir 300/100 mg plus omeprazole reduced atazanavir AUC and Cmin by 42% and 46%, respectively. Increasing the atazanavir/ritonavir dose to 400/100 mg attenuated the effect of omeprazole, resulting in approximately 30% lower atazanavir Cmin, with all individual Cmin values exceeded by greater than 10‐fold the population mean protein binding‐adjusted EC90 against wild‐type HIV. The effect of omeprazole on atazanavir/ritonavir 400/100 mg was similar whether given 1 hour prior to atazanavir/ritonavir or separated by 12 hours. No unexpected adverse events were noted. This study found that omeprazole 20 mg once daily has significantly less profound effects on atazanavir pharmacokinetics than previously observed with omeprazole 40 mg.