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A Comparative Pharmacokinetic Study in Healthy Volunteers of the Effect of Carbamazepine and Oxcarbazepine on Cyp3a4
Author(s) -
Andreasen AstridHelene,
Brøsen Kim,
Damkier Per
Publication year - 2007
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2007.00924.x
Subject(s) - carbamazepine , quinidine , oxcarbazepine , pharmacokinetics , cyp3a4 , crossover study , pharmacology , medicine , anticonvulsant , cmax , oral administration , drug interaction , epilepsy , metabolism , cytochrome p450 , alternative medicine , pathology , psychiatry , placebo
Summary: 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 ½ 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.