Abstract

Interaction Study of the Combined Use of Paroxetine and Fosamprenavir-Ritonavir in Healthy Subjects ▿ Manon J. van der Lee 1 , 2 , † , * , Audrey A. M. Blenke 1 , 2 , † , Gerard A. Rongen 3 , Corrien P. W. G. M. Verwey-van Wissen 1 , 2 , Peter P. Koopmans 2 , 4 , Cristina Pharo 5 and David M. Burger 1 , 2 1 Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 2 Nijmegen University Centre for Infectious Diseases, Nijmegen, the Netherlands 3 Clinical Research Centre Nijmegen, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 4 Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 5 GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom 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.