Effect of omeprazole on the plasma concentrations of indinavir when administered alone and in combination with ritonavir

Abstract

Purpose-The effects of omeprazole on indinavir when administered alone or in combination with ritonavir were evaluated.Methods-Fourteen men and women age 18-55 years not infected with human immunodeficiency virus who met study qualifications were randomized to receive placebo, 20 mg of omeprazole, or 40 mg of omeprazole daily. After seven days, the single-dose pharmacokinetic profile of an 800-mg dose of indinavir alone or in combination with 200 mg of ritonavir was evaluated. Study participants received each of four study regimens in one of four randomly assigned orders. Blood samples were collected, and plasma indinavir and ritonavir concentrations were analyzed using high-performance liquid chromatography. Conclusion-The AUC of indinavir was substantially decreased in healthy volunteers who received omeprazole 20 or 40 mg daily for seven days before the administration of a single 800-mg dose of indinavir. Concomitant administration of ritonavir 200 mg with indinavir in participants receiving omeprazole led to a significant increase in the AUC of indinavir. Results-The Index termsAntiretroviral agents; Blood levels; Dosage; Drug interactions; Gastrointestinal drugs; HIV infections; Indinavir; Omeprazole; Pharmacokinetics; Ritonavir Protease inhibitors (PIs) exhibit a high degree of pharmacokinetic variability in patients infected with the human immunodeficiency virus (HIV). 1,2 Large interindividual differences in drug absorption and elimination in HIV-infected patients have been primarily attributed to constitutive or altered drug metabolizing enzymes, P-glycoprotein transporter activities, and poor drug solubility. 3 With the PIs indinavir and atazanavir, changes in gastric pH can alter drug absorption. 4,5 Specifically, when these PIs are administered with medications that Address correspondence to Dr. Kashuba at the School of Pharmacy, CB7360, University of North Carolina, Chapel Hill, NC 27599-7360 (akashuba@unc.edu increase gastric pH, such as histamine (H 2 )-receptor antagonists and proton-pump inhibitors (PPIs), bioavailability can decrease by up to 76%. 4,6 A survey of 200 HIV-infected patients was performed to assess their use of drugs that affect gastric acidity. 7 Fifty-six percent of HIV-infected patients who had recently begun highly active antiretroviral therapy (HAART) had taken nonprescription acid-reducing agents, and 39% had used both nonprescription and prescription products for acid reduction. Forty-six percent of patients on a PI-containing regimen had used PPIs or H 2 -receptor antagonists once they started HAART, and 35% had used them within the previous 12 months. This widespread use of acid-reducing agents among HIV-infected patients has implications for drug interactions with antiretrovirals and other medications that require an acidic environment for adequate dissolution and absorption.Ritonavir is a cytochrome P-450 (CYP) isoenzyme 3A and P-glycoprotein inhibitor which, when used in low doses, can increase the exposure of concomitantly administered PIs. The concomitant ad...

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

“…13 Significant pharmacokinetic interactions can result between acid-suppressing therapies and some PIs, most notably atazanavir and indinavir, whereas others such as lopinavir, fosamprenavir, and darunavir are largely free of such interactions. [16][17][18][19][20] Both atazanavir and indinavir depend on an acidic gastric environment for adequate in vivo dissolution and 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%.…”

Drug–Drug Interactions Related to Altered Absorption and Plasma Protein Binding: Theoretical and Regulatory Considerations, and an Industry Perspective

“…Half of these drugs showed DDIs resulting in greater than 25% reduction in drug exposure (area under plasma concentration–time curve, AUC) as a consequence of pH‐associated decreases in solubility . Substantial reductions (∼50%–100%) in drug exposure have been reported following coadministration of acid‐reducing agents with indinavir and atazanavir . Consistent with the premise that the effects are because of pH‐dependent solubility, lopinavir, a neutral antiretroviral drug is not subject to acid‐reducing agent DDIs .…”

Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management

“…With respect to significant omeprazole–indinavir DDIs, concomitant 200 mg ritonavir therapy may reverse this adverse interaction, as it can substantially inhibit clearance of indinavir, presumably via mechanism-based inhibition of CYP3A-mediated metabolism of indinavir or, possibly, inhibition of P-glycoprotein 31–33. As described in the package insert for Crixivan® (indinavir sulfate; Merck and Co, Inc, Whitehouse Station, NJ, USA), comedicated histamine 2 antagonist cimetidine (600 mg twice daily) minimally affected the AUC of a single 400 mg dose of indinavir.…”