Pharmacokinetic interaction between valproic acid and meropenem

Excerpt

Sir: The metabolism of valproic acid (VPA), a widely prescribed antiepileptic drug, is rather complex. Pharmacokinetic interactions with other drugs is due the ability of VPA to inhibit several hepatic enzymes, and in turn other drugs may also induce its hepatic metabolism. Recent reports outline a significant interaction between carbapenems and VPA with as a result a marked decrease in serum VPA concentrations and possible adverse neurological manifestations [1, 2, 3, 4]. We had a similar experience in two cases. The first was that of a 30-year-old-man admitted after severe head trauma with subarachnoid hemorrhage and cerebrospinal fluid fistula, and VPA was prescribed for seizure prophylaxis. Serum VPA concentration remained within therapeutic range for 21 days until meropenem was introduced (8000 mg/day) for the treatment of meningitis complicated by brain abscess due to Acinetobacter baumanii. Serum VPA level felt from 61 to 17.2 µg/ml in less than 36 h, and VPA was not detectable after 5 days of meropenem therapy, while the patient was receiving a continuous VPA infusion at a rate of 150 mg/h. As seizures did not occur, VPA was definitely stopped 6 days later. The second patient, a 77-year-old man, was admitted to the ICU after generalized tonic-clonic seizures developing to status epilepticus related to a recent right parietal stroke. Initial antiepileptic regimen consisted of a combination of VPA (15 mg/kg as a loading dose, followed by a continuous infusion at an hourly rate of 1 mg/kg), levetiracetam (3000 mg/day), and midazolam (infusion at an hourly rate of 0.2 mg/kg). Midazolam was continued until electroencephalography confirmed the absence of epileptic activity (day 16). During this period serum VPA concentration was within therapeutic range. On day 18 meropenem (6000 mg/day) was administered to treat sepsis secondary to urinary tract infection due to multiresistant Pseudomonas aeruginosa. By the next day the serum VPA concentration markedly decreased (Fig. 1). The dose of VPA was increased to 2 mg/kg per hour without any rise in VPA levels. Nevertheless, no seizures occurred, and the patient’s neurological condition continued to improve. Meropenem was discontinued after 8 days, and soon after the serum VPA concentration returned to values similar to those observed before meropenem therapy.

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