title: Effect of low-dose omeprazole (20 mg daily) on the pharmacokinetics of multiple-dose atazanavir with ritonavir in healthy subjects.
abstract: 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 (C(min)) 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 C(min) 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 C(min), with all individual C(min) values exceeded by greater than 10-fold the population mean protein binding-adjusted EC(90) 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.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, USA. li.zhu@bms.com
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.forename: Lisa
authors.initials: L
authors.lastname: Mahnke
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Agarwala
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dragone
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D009853:Omeprazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D054328:Proton Pump Inhibitors; D011725:Pyridines; D000069446:Atazanavir Sulfate; D009853:Omeprazole; D019438:Ritonavir