Reduced valproic acid concentrations in patients receiving carbapenems: meta-analysis

Abstract

Introduction: The administration of valproic acid (VPA) with a carbapenem antibiotic results in reduced VPA concentrations. This article aims to examine the existing literature on the impact of the co-medication between VPA and carbapenem, and conduct VPA model based dose optimisation using simulated participants.

Methods: A literature review was conducted utilising Medline™ (via PubMed^®), ResearchGate^®, and Google Scholar™ (using the following search terms: valproate, valproic acid, carbapenem, ertapenem, meropenem, imipenem, and valproate drug-drug interaction), to obtain clinical studies and case reports reporting on the interaction between VPA and carbapenems. Additionally, a manual search of prominent journals for articles cited in PubMed and Google Scholar was performed. Publications were included up to March 2025 with no lower limit enforced. Model-based simulations for sodium valproate were conducted with RxODE2 (R package) using RStudio.

Results and discussion: Our analysis of 13 pharmacokinetics studies and 15 case reports indicates that carbapenem antibiotics, such as meropenem, ertapenem, and imipenem, can reduce the serum levels of VPA, leading to subtherapeutic concentrations and seizures in certain patients. About a 60–90% increase in VPA clearance was observed. Doses of 465–1 053 mg (10–15 mg/kg/day) were shown to be subtherapeutic for patients taking carbapenems, with doses from 1 227–2 725 mg (25 mg/kg/day) only reaching therapeutic targets, and are most likely to increase the drug’s side-effects profile.

Conclusions: In general, it is advisable to avoid the concurrent use of carbapenem antibiotics and VPA derivatives due to the possibility of a drug-drug interaction that causes sub-therapeutic valproate serum levels. Alternative antimicrobial agents should be considered instead of carbapenems; however, if the use of a carbapenem is necessary, an additional antiepileptic is suggested.