A PHARMACOKINETIC INTERACTION BETWEEN CARBAMAZEPINE AND OLANZAPINE - OBSERVATIONS ON POSSIBLE MECHANISM

Objective: Olanzapine is a novel antipsychotic, which is effective aga inst both the positive and negative symptoms of schizophrenia and caus es fewer extrapyramidal adverse effects than conventional antipsychoti cs. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, sin ce these agents are likely to be used concomitantly in the treatment o f manic psychotic disorder. Method: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunte ers. The first dose of olanzapine (10 mg) was taken alone and the Seco nd dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6 beta-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. Results: The dose of olanzapine given a fter a 2-week pretreatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for C- max and AUC were significantly lower after the second dose, the elimin ation half-life was significantly shorter, and the clearance and volum e of distribution were significantly increased. Conclusion: Carbamazep ine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2, Since CYP1A2 plays a role in the metabolic clearance of o lanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolis m of olanzapine. The interaction is not considered to be of clinical s ignificance because olanzapine has a wide therapeutic index, and the c hanges in plasma concentration of olanzapine are within the fourfold v ariation that occurs without concern for safety in a patient populatio n.