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Possible Interaction Between Lopinavir/Ritonavir and Valproic Acid Exacerbates Bipolar Disorder

Assistant Clinical Professor and Pharmacist, Faculty of Pharmacy, University of Montréal; Immunodeficiency Service, Montréal Chest Institute, McGill University Health Centre, Montréal, Québec, Canada

Marie-Josée Brouillette, MD

Psychiatrist, Immunodeficiency Service, Montréal Chest Institute, Department of Psychiatry, McGill University Health Centre

Marie-Soleil Delisle, BPharm

Pharmacy Resident, Department of Pharmacy, McGill University Health Centre

James Allan, MD

Infectious Diseases Specialist, Immunodeficiency Service, Montréal Chest Institute, McGill University Health Centre

Reprints: Ms. Sheehan, Faculty of Pharmacy, University of Montréal, C.P. 6128, succursale Centre-Ville, Montréal H3C 3J7, Québec, Canada, fax 514/843-2092, nancy.sheehan{at}umontreal.ca

OBJECTIVE: To describe a case of exacerbated mania potentially related to an interaction between lopinavir/ritonavir and valproic acid (VPA) and propose a mechanism of action for this interaction.

CASE SUMMARY: A 30-year-old man with bipolar disorder and HIV initiated treatment with lopinavir/ritonavir, zidovudine, and lamivudine. Prior to beginning therapy with these antiretrovirals, he was receiving VPA 250 mg 3 times daily, with his most recent VPA concentration measured at 495 µmol/L. Twenty-one days after starting antiretroviral treatment, he became increasingly manic. His VPA concentration at admission was 238 µmol/L, a 48% decrease. The daily VPA dose was increased to 1500 mg, and olanzapine was introduced. The VPA concentration following this dose escalation was 392 µmol/L, and the patient improved clinically.

DISCUSSION: Fifty percent of VPA is metabolized by glucuronidation, 40% undergoes mitochondrial ß-oxidation, and less than 10% is eliminated by the cytochrome P450 isoenzymes. Ritonavir can induce glucuronidation of several medications including ethinyl estradiol, levothyroxine, and lamotrigine. We believe that ritonavir-mediated induction of VPA glucuronidation resulted in a decrease in VPA concentrations and efficacy. An objective causality assessment suggested that the increased mania was probably related to the decrease in VPA concentration and that a possible interaction exists between lopinavir/ritonavir and VPA.

CONCLUSIONS: A potential interaction exists between VPA and all ritonavir-boosted antiretroviral regimens. Clinicians should monitor patients closely for a decreased VPA effect when these medications are given concomitantly.

Key Words: glucuronidation, lopinavir, ritonavir, valproic acid

Published Online, December 20, 2005. www.theannals.com, DOI 10.1345/aph.1G418

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