A Case of Pharmacokinetic Interference in Comedication of Clozapine and Valproic Acid

In 4 - 6 % of treatment histories, clozapine induces generalized seizures by reducing the seizure threshold. Despite the knowledge of high risks combined therapy (such as bone marrow suppression, pathological EEG changes), some authors even suggest the prophylactic combination with anticonvulsants in high dose treatment of clozapine. We report a case of a 33-year-old female patient, a heavy smoker, suffering from mixed schizoaffective disorder from 1989 onwards. At her 8th admission in 1998, she was rehospitalized after experiencing her first generalized seizure under clozapine treatment, although no seizure phenomenon or other relevant side-effects under several previous clozapine therapies had been observed. Therefore, she received a valproic acid co-medication during her clozapine therapy. Based on therapeutic drug monitoring of clozapine (weekly) under compliance-controlled conditions, the serum levels of clozapine significantly decreased, probably induced by valproic acid. According to the literature, this case report might support the clinical relevance of therapeutic drug monitoring when clozapine therapy is combined with valproic acid as co-medication.

References

• 1 Bertilsson L, Carrillo J A, Dahl M L, Ilerena A, Alm C, Bondersson U. et al . Clozapine disposition covaries with CYP1 A2 activity determined by a caffeine test.  Br J Clin Pharmacol. 1994;  38 471-473
• 2 Centorrino F, Baldasserini R J, Kando J, Frankenburg F R, Volpicelli S A, Puopolo P R, Flood J. Serum concentrations of clozapine and its major metabolites: effects of cotreatment with Fluoxetine or Valproate.  Am J Psychiatry. 1994;  151 123-125
• 3 Dose M. Behandlung der Therapieresistenzen mit Clozapin. In: Naber D, Müller-Spahn F (eds) Clozapin. Pharmakologie und Klinik eines atypischen Neuroleptikums.  Berlin, Heidelberg, New York, Tokyo; Springer 1995: 19-27
• 4 Edge S C, Markovitz J S, De Vane C L. Clozapine drug-drug interaction; a review of the literature.  Hum Psychopharmacol. 1997;  12 5-20
• 5 Facciolà G, Avenoso A, Scordo M G, Madia A G, Ventimiglia A, Perucca E, Spina E. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders.  Ther Drug Monit. 1999;  21 341-345
• 6 Finley P, Warner D. Potential impact of valproic acid therapy on clozapine disposition.  Biol Psychiatry. 1994;  36 487-488
• 7 Glue P, Banfield C H. Psychiatry, Psychopharmacology and P 450 s.  Hum Psychopharmacol. 1996;  11 97-114
• 8 Haller E, Binde R L. Clozapine and seizures.  Am J Psychiatry. 1990;  147 1069-1071
• 9 Levy R H, Rettenmeier A W, Anderson G D, Wilensky A J, Friel P N, Boillie T A. et al . Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of enevalproate, a hepatotoxic metabolite of valproic acid.  Clin Pharmacol Ther. 1990;  48 225-235
• 10 Longo L P, Salzman C. Valporic Acid Effects on Serum Concentrations of Clozapine and Norclozapine.  Am J Psychiatry. 1995;  152 650
• 11 Park B K, Kitterinham N R, Pirmohamed M, Tucker G T. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications.  Br J Clin Pharmacol. 1996;  41 477-491