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Department of Pharmacy, University Hospital Gasthuisberg, Leuven, Belgium
Department of Neurology, University Hospital Gasthuisberg
Medical Intensive Care Unit, University Hospital Gasthuisberg
Associate Professor, Medical Intensive Care Unit, University Hospital Gasthuisberg
Associate Professor, Department of Pharmacy, University Hospital Gasthuisberg
Associate Professor, Department of Neurology, University Hospital Gasthuisberg
Reprints: Dr. Spriet, Department of Pharmacy, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium, fax 0032 16 34 30 85, Isabel.Spriet{at}uz.kuleuven.be
BACKGROUND: Valproate and meropenem are frequently used in the intensive care unit to treat seizures and serious infections, respectively. Several case reports have described a remarkable interaction between the drugs when administered concurrently. The interaction leads to a significant drop in plasma concentrations of valproate within 24 hours and relapse of seizures in some patients.
OBJECTIVE: To evaluate a consecutive population of hospitalized patients who were simultaneously treated with meropenem and valproate and assess the effect on epileptic activity.
METHODS: A retrospective study of an 18 month period was performed to assess the extent and clinical impact of this interaction. To assess the relevance of the interaction, the time-relationship between the drop in plasma concentrations and relapse in seizure activity and/or deterioration of electroencephalogram recordings was determined. We investigated other contributing proconvulsive cofactors and concomitant antiepileptic treatment. Drug interaction probability scale (DIPS) scores were calculated.
RESULTS: Thirty-nine patients were treated simultaneously with valproate and meropenem. The pharmacokinetic interaction was observed in all 39 patients, with an average drop in valproate plasma concentrations of 66%. The decrease occurred within 24 hours, as shown in 19 patients who had daily plasma concentration monitoring. The clinical impact of the interaction could not be assessed in 19 (49%) patients due to death (n = 13) or incomplete charts (n = 6). In the remaining 20 (51%) patients, DIPS scores were calculated and clinical relevance was assessed. The interaction was considered to be probable in 16 patients and possible in 4, as calculated by the DIPS. The interaction contributed to electroclinical deterioration in 11 patients.
CONCLUSIONS: The pharmacokinetic interaction between valproate and meropenem was present in all patients and led to a drop of valproate concentrations with an average of 66% within 24 hours. This interaction was clinically relevant with electroclinical deterioration in 55% of patients. To avoid patients' possible neurologic deterioration, meropenem and valproate should not be administered together.
Key Words: epilepsy, interaction, meropenem, valproate
Published Online, July 3, 2007. www.theannals.com, DOI 10.1345/aph.1K079
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  S. Haroutiunian, Y. Ratz, B. Rabinovich, M. Adam, and A. Hoffman Valproic Acid Plasma Concentration Decreases in a Dose-Independent Manner Following Administration of Meropenem: A Retrospective Study J. Clin. Pharmacol., November 1, 2009; 49(11): 1363 - 1369. [Abstract] [Full Text] [PDF]
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