title: Interaction study of the combined use of paroxetine and fosamprenavir-ritonavir in healthy subjects.
abstract: Human immunodeficiency virus-infected patients have an increased risk for depression. Despite the high potential for drug-drug interactions, limited data on the combined use of antidepressants and antiretrovirals are available. Theoretically, ritonavir-boosted protease inhibitors may inhibit CYP2D6-mediated metabolism of paroxetine. We wanted to determine the effect of fosamprenavir-ritonavir on paroxetine pharmacokinetics and vice versa and to evaluate the safety of the combination. Group A started with 20 mg paroxetine every day for 10 days; after a wash-out period of 16 days, subjects received paroxetine (20 mg every day) plus fosamprenavir-ritonavir (700/100 mg twice a day) from days 28 to 37. Group B received the regimens in reverse order. On days 10 and 37, pharmacokinetic curves were recorded. Twenty-six healthy subjects (18 females, 8 males) were included. Median (range) age and weight were 44.4 (18.2 to 64.3) years and 68.8 (51.0 to 89.4) kg. Three subjects were excluded (two because of adverse events; one for nonadherence). Addition of fosamprenavir-ritonavir to paroxetine resulted in a significant decrease in paroxetine exposure: the geometric mean ratios (90% confidence intervals) of paroxetine plus fosamprenavir-ritonavir to paroxetine alone were 0.45 (0.41 to 0.49) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (C(max)), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (t(1/2)). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC(0-12), C(max), C(min), and t(1/2) of amprenavir and ritonavir were similar to those of historical controls. No serious adverse events occurred. Fosamprenavir-ritonavir reduced total paroxetine exposure by 55%. This is partly explained by protein displacement of paroxetine. We think that this interaction is clinically relevant and that titration to a higher dose of paroxetine may be necessary to accomplish the needed antidepressant effect.
authors.affiliation: Department of Clinical Pharmacy, Radboud University Medical Centre Nijmegen, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. m.vanderlee@akf.umcn.nl
authors.forename: Manon J
authors.initials: MJ
authors.lastname: van der Lee
authors.forename: Audrey A M
authors.initials: AA
authors.lastname: Blenke
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.forename: Corrien P W G M
authors.initials: CP
authors.lastname: Verwey-van Wissen
authors.forename: Peter P
authors.initials: PP
authors.lastname: Koopmans
authors.forename: Cristina
authors.initials: C
authors.lastname: Pharo
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D005663:Furans; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010755:Organophosphates / Q000009:adverse effects / Q000493:pharmacokinetics*; D017374:Paroxetine / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D018687:Antidepressive Agents, Second-Generation; D002219:Carbamates; D005663:Furans; D010755:Organophosphates; D013449:Sulfonamides; D017374:Paroxetine; D019438:Ritonavir; C426859:fosamprenavir