Liverpool HIV Interactions

No Interaction Expected

Efavirenz (EFV)

Valproate semisodium (Divalproex sodium)

Quality of Evidence: Very Low

Summary:

Coadministration with valproate semisodium (divalproex semisodium) has not been studied but studies with valproic acid suggest a clinically significant interaction is unlikely. Valproate semisodium (divalproex semisodium) is a stable coordination compound comprised of sodium valproate and valproic acid and dissociates to the valproate ion in the gastrointestinal tract. Valproate is mainly glucuronidated by UGTs 1A6, 1A9 and 2B7 and metabolized by CYP2C9 and CYP2C19. Coadministration of efavirenz (600 mg once daily) and valproic acid (250 mg twice daily) had no significant effect on efavirenz AUC, Cmin or Cmax, or on valproate trough or 8 h concentrations (n=11). A retrospective analysis of a TDM registry showed no significant effect of valproic acid on efavirenz trough concentrations (n=2). The product label for efavirenz recommends that patients should be monitored for seizure control.

Description:

Coadministration of valproic acid (250 mg twice daily) and efavirenz (600 mg once daily) had no clinically significant effect on efavirenz pharmacokinetics. Limited data suggest there is no clinically significant effect on valproic acid pharmacokinetics. No dosage adjustment is necessary for efavirenz. Patients should be monitored for seizure control.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

Following the unexpected drug-drug interaction between dolutegravir and valproic acid, plasma concentrations of several antiretrovirals drugs were analyzed when administered in presence and absence of valproic acid. Drug concentrations were obtained from the TDM registry of the University Hospital of Torino. A total of 134 individuals receiving concomitantly valproic acid and antiretroviral drugs were identified (dolutegravir, n=29; raltegravir, n=27; atazanavir, n=24; darunavir, n=13; lopinavir, n=4); etravirine, n=10; rilpivirine, n=7; nevirapine, n=3; efavirenz, n=2; maraviroc, n=17). With the exception of dolutegravir, no significant decrease in plasma exposure was observed for the other antiretrovirals.

Antiretroviral concentrations in the presence and absence of valproic acid. Calcagno A, Cusato J, Ferrara M et al. J Antimicrob Agents 2020; 75:1969-1971.

Coadministration of efavirenz (600 mg once daily) and valproic acid (250 mg twice daily) was studied in 11 HIV+ subjects. There were no significant differences in efavirenz AUC (39.86 vs 39.00 µg/ml.h), Cmin (1.44 vs 1.32 µg/ml) or Cmax (2.43 vs 2.03 µg/ml) when given with valproic acid. There was no apparent effect of efavirenz on valproic acid trough or 8h post dose concentrations.

Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. DiCenzo R, Peterson D, Cruttenden, et al. Antimicrob Agents Chemother, 2004, 48: 4328-4331.

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