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Antimicrobial Agents and Chemotherapy, November 2007, p. 4098-4104, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01243-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Interaction Study of the Combined Use of Paroxetine and Fosamprenavir-Ritonavir in Healthy Subjects{triangledown}

Manon J. van der Lee,1,2,{dagger}* Audrey A. M. Blenke,1,2,{dagger} 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. Burger1,2

Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands,1 Nijmegen University Centre for Infectious Diseases, Nijmegen, the Netherlands,2 Clinical Research Centre Nijmegen, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands,3 Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands,4 GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom5

Received 4 October 2006/ Returned for modification 31 May 2007/ Accepted 28 August 2007

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 (AUC0-24), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (Cmax), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (t1/2). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC0-12, Cmax, Cmin, and t1/2 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.

* Corresponding author. Mailing address: Department of Clinical Pharmacy, 864 Radboud University Medical Centre Nijmegen, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. Phone: 31 24 3616405. Fax: 31 24 3668755. E-mail: m.vanderlee{at}akf.umcn.nl

{triangledown} Published ahead of print on 10 September 2007.

{dagger} Both authors contributed the same amount of work to this paper.

Antimicrobial Agents and Chemotherapy, November 2007, p. 4098-4104, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01243-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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