Journal
EPILEPSIA
Volume 48, Issue 3, Pages 490-496Publisher
WILEY
DOI: 10.1111/j.1528-1167.2007.00924.x
Keywords
carbamazepine; oxcarbazepine; drug-drug interaction; P450 induction; CYP3A4
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Purpose: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. Results: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36-164; p = 0.0022) and 181% (CI: 120-260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139-187, p < 0.0001) (OXCZ) and 222% (CI: 192-257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16-40, p = 0.0018) (OXCZ) and 33% (CI: 18-45, p = 0.0020) (CBZ). T-1/2 decreased by means of 12% (CI: 6-17, p < 0.0014) (OXCZ) and 32% (CI: 25-38, p < 0.0001) (CBZ). t(max) was not changed in either period. Conclusion: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance.
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