title: Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
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.
authors.affiliation: Maternal Child Adolescent Program, University of Southern California, 1640 Marengo Street, Los Angeles, CA 90033, USA. mneely@usc.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
authors.forename: Laurent
authors.initials: L
authors.lastname: Decosterd
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fayet
authors.forename: Janice Soo Fern
authors.initials: JS
authors.lastname: Lee
authors.forename: Ashley
authors.initials: A
authors.lastname: Margol
authors.forename: Meera
authors.initials: M
authors.lastname: Kanani
authors.forename: Julia
authors.initials: J
authors.lastname: di Iulio
authors.forename: Tido
authors.initials: T
authors.lastname: von Schoen-Angerer
authors.forename: Roger
authors.initials: R
authors.lastname: Jelliffe
authors.forename: Alexandra
authors.initials: A
authors.lastname: Calmy
mesh_terms: D000328:Adult; D000069446:Atazanavir Sulfate; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000068898:Raltegravir Potassium; D055815:Young Adult
chemical_list: D019428:HIV Integrase Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000069446:Atazanavir Sulfate
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