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Antimicrobial Agents and Chemotherapy, November 2004, p. 4328-4331, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4328-4331.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

Robert DiCenzo,1,2* Derick Peterson,2 Kim Cruttenden,2 Gene Morse,1 Garret Riggs,2 Harris Gelbard,2 and Giovanni Schifitto2

University at Buffalo, Buffalo,1 University of Rochester, Rochester, New York2

Received 26 January 2004/ Returned for modification 18 March 2004/ Accepted 30 June 2004

Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C0 and 8-h VPA concentrations versus the control (n = 11) were –1.0 (–9.4, 7.4) µg/ml and –2.1 (–11.1, 6.9) µg/ml for EFV (n = 10) and –5.0 (–13.2, 3.3) µg/ml and –6.7 (–17.6, 4.2) µg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

* Corresponding author. Mailing address: University of Rochester Medical Center, Clinical Pharmacology Unit, 601 Elmwood Ave., Box 315, Room 1.6124, Rochester, NY 14642. Phone: (585) 273-2885. Fax: (585) 275-7896. E-mail: robert_dicenzo{at}urmc.rochester.edu.

Antimicrobial Agents and Chemotherapy, November 2004, p. 4328-4331, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4328-4331.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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