Ritonavir + Valproic Acid = Precautionary

Effect on Concentration

Ritonavir
Increase
Applies within class?
No
Valproic Acid
No change
Applies within class?
No

Pharmacologic Effects

Ritonavir
Effect
N/A
Applies within class?
No
Valproic Acid
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 25-Jun-2018

Summary

Sources

Lopinavir/Ritonavir versus Valproic Acid ^

Study Design

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.

Study Results

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.

Study Conclusions

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. Case studies do suggest that ritonavir may induce glucuronidation of other anticonvulsants, and reports of loss of mania control on valproic acid exist. Monitoring for safety and efficacy are recommended in these instances.

References

Dicenzo R, et al. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrobial Agents And Chemotherapy. 2004; : 4328-4331.