Liverpool HIV Interactions

Potential Interaction

Lopinavir/ritonavir (LPV/r)

Valproate semisodium (Divalproex sodium)

Quality of Evidence: Very Low

Summary:

Coadministration with valproate semisodium (divalproex semisodium) has not been studied. 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 lopinavir/ritonavir (400/100 mg twice daily) and valproic acid (250 mg twice daily) to 8 HIV+ subjects increased lopinavir AUC by ~38%. No apparent effect of lopinavir/ritonavir on valproate concentrations was observed. A retrospective analysis of a TDM registry showed no significant effect of valproic acid on lopinavir trough concentrations (n=4). However, there is a case report of a 48% decrease in valproate concentration in previously stable patient who developed exacerbated mania on starting lopinavir/ritonavir; dose increase of valproic acid was required.

Description:

Coadministration may decrease valproate concentrations. Patients should be monitored closely for a decreased VPA effect when Kaletra and valproic acid or valproate are given concomitantly.

Kaletra Summary of Product Characteristics, AbbVie Ltd, January 2021.

Coadministration may decrease valproate concentrations, or have no effect on valproate. A dose increase of valproate may be needed when coadministered with Kaletra.

Kaletra Prescribing Information, AbbVie Inc, October 2020.

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 lopinavir/ritonavir (400/100 mg twice daily) and valproic acid (250 mg twice daily) was studied in 8 HIV+ subjects. Lopinavir exposure was higher in 6/8 subjects when given with valproic acid; there was a median increase in lopinavir AUC of ~38% (61.02 vs 106.87 ng/ml.h). There were no significant differences in lopinavir Cmin (6.81 vs 10.7 ng/ml) or Cmax (12.4 vs 16.5 ng/ml) when given with valproic acid. There was no apparent effect of lopinavir/ritonavir 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.

A case of exacerbated mania potentially related to an interaction between lopinavir/ritonavir and valproic acid was reported in a 30 year old man. The subject was stable on valproic acid (250 mg, three times daily) prior to the initiation of HIV therapy with zidovudine, lamivudine and lopinavir/ritonavir. Three weeks after commencing HIV therapy, he became increasingly manic and his valproic acid concentration had decreased by 48% (from 495 to 238 µmol/L). The valproic acid was increased to 1500 mg daily and olanzapine was introduced; this resulted in a valproic acid concentration of 392 µmol/L and clinical improvement. Inhibition of valproic acid glucuronidation by ritonavir was proposed as the mechanism of interaction.

Possible interaction between lopinavir/ritonavir and valproic acid exacerbates bipolar disorder. Sheehan NL. Ann Pharmcother, 2005, 40: 147-150.

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