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.