Identification of a Safe and Tolerable Carbamazepine Dosing Paradigm that Facilitates Effective Evaluation of CYP3A4 Induction.

Carbamazepine (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug-drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4-sensitive index substrate midazolam (MDZ). This was a fixed-sequence arm of an open-label, phase I study (NCT04840888). Healthy participants (n = 15) aged 18-63 years received oral doses of 1.2 mg MDZ alone (Day 1), CBZ b.i.d. alone (100 mg Days 2-4; 200 mg Days 5-7; 300 mg Days 8-10 and 12-13), and 300 mg CBZ b.i.d. plus 1.2 mg MDZ (Days 11 and 14). One participant (6.7%) experienced constipation due to treatment with CBZ plus MDZ on Day 11. One participant (6.7%) experienced urticaria (Days 12-13), and two participants (13.3%) experienced somnolence (Days 8-10) due to treatment with 300 mg CBZ b.i.d. alone. All AEs were mild. For MDZ, the geometric mean (90% CI) ratio (vs. Day 1) of the area under the curve (AUC 0-∞) was 0.28 (0.24-0.31) on Day 11 and 0.26 (0.23-0.29) on Day 14. The AUC (0-12 hours) of CBZ was 114,000 ng∙h/mL on Day 11 and 105,000 ng∙h/mL on Day 14. Steady-state concentrations of CBZ and induction of CYP3A4 were achieved on Day 11. The data are consistent with predictions of physiologically-based pharmacokinetic models in Simcyp. The 9-day dosing regimen for CBZ induction was well-tolerated by healthy participants, supporting the use of a shorter CBZ regimen for CYP3A4 induction studies.