Pharmacokinetics and Pharmacogenomics of Once-Daily Raltegravir and Atazanavir in Healthy Volunteers

Author:

Neely Michael12,Decosterd Laurent3,Fayet Aurélie3,Lee Janice Soo Fern4,Margol Ashley5,Kanani Meera5,di Iulio Julia3,von Schoen-Angerer Tido4,Jelliffe Roger2,Calmy Alexandra46

Affiliation:

1. University of Southern California, Maternal Child Adolescent Program, Los Angeles, California

2. University of Southern California, Laboratory of Applied Pharmacokinetics, Los Angeles, California

3. Centre Hospitalier Universitaire Vaudois, Division of Clinical Pharmacology Laboratory, Department of Medicine, Lausanne, Switzerland

4. Médecins Sans Frontières, Campaign for Access to Essential Medicines, Geneva, Switzerland

5. University of Southern California, Pediatrics, Los Angeles, California

6. Geneva University Hospital, HIV Unit, Geneva, Switzerland

Abstract

ABSTRACT Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ≥3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C tau , or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C tau , area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), and raltegravir-glucuronide/raltegravir AUC 0-12 were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C tau with a once-daily raltegravir dose of 400 mg similar to the C tau with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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