Possible interaction between lopinavir/ritonavir and valproic Acid exacerbates bipolar disorder.
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.


METHODS
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 micromol/L. Twenty-one days after starting antiretroviral treatment, he became increasingly manic. His VPA concentration at admission was 238 micromol/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 micromol/L, and the patient improved clinically.


CONCLUSIONS
Fifty percent of VPA is metabolized by glucuronidation, 40% undergoes mitochondrial beta-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.
Sheehan
Nancy L
NL
Faculty of Pharmacy, University of Montréal, Montréal, Québec, Canada. nancy.sheehan@umontreal.ca
Brouillette
Marie-Josée
MJ
Delisle
Marie-Soleil
MS
Allan
James
J
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D001714:Bipolar Disorder / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015658:HIV Infections / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy; D006526:Hepatitis C / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy; D006801:Humans; D061466:Lopinavir; D008297:Male; D011744:Pyrimidinones / Q000009:adverse effects* / Q000627:therapeutic use; D019438:Ritonavir / Q000009:adverse effects* / Q000627:therapeutic use; D014635:Valproic Acid / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use
D011744:Pyrimidinones; D061466:Lopinavir; D014635:Valproic Acid; D019438:Ritonavir