title: Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers.
abstract: Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands. Electronic address: birgit.jacobs@catharinaziekenhuis.nl.
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Jacobs
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands.
authors.forename: Angela P H
authors.initials: AP
authors.lastname: Colbers
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Velthoven-Graafland
authors.affiliation: Department of Pharmacology & Toxicology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands.
authors.forename: Bas J J W
authors.initials: BJ
authors.lastname: Schouwenberg
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Geert Grooteplein 10, Nijmegen, The Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002219:Carbamates / Q000008:administration & dosage*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D005663:Furans; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010755:Organophosphates / Q000008:administration & dosage*; D019438:Ritonavir / Q000008:administration & dosage*; D044967:Serum / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013449:Sulfonamides / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D014150:Antipsychotic Agents; D002219:Carbamates; D005663:Furans; D010755:Organophosphates; D013449:Sulfonamides; D001569:Benzodiazepines; D000077152:Olanzapine; D019438:Ritonavir; C426859:fosamprenavir
keywords: Drug–drug interaction; Fosamprenavir; Olanzapine; Pharmacokinetics; Protease inhibitor