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). T1/2 decreased by means of 12% (CI: 6-17, p<0.0014) (OXCZ) and 32% (CI: 25-38, p<0.0001) (CBZ). tmax 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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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). T1/2 decreased by means of 12% (CI: 6-17, p<0.0014) (OXCZ) and 32% (CI: 25-38, p<0.0001) (CBZ). tmax 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.
Authors: Lisa M Almond; Sophie Mukadam; Iain Gardner; Krystle Okialda; Susan Wong; Oliver Hatley; Suzanne Tay; Karen Rowland-Yeo; Masoud Jamei; Amin Rostami-Hodjegan; Jane R Kenny Journal: Drug Metab Dispos Date: 2016-03-29 Impact factor: 3.922