Associate Vice President Eli Lilly and Company Indianapolis, Indiana, United States
Background: Due to impurities exceeding the acceptable limit for rifampin products, there is a need to leverage alternate CYP3A inducers in drug-drug interaction (DDI) studies (1). Carbamazepine (CBZ) is the recommended choice to evaluate the impact of CYP3A inducers in DDI studies; however, traditional CBZ dosing paradigms can lead to numerous adverse events (AEs) (2). This study tested a CBZ dosing paradigm using the known sensitive index substrate for CYP3A, midazolam (MDZ), to identify a safe and tolerable regimen that also reliably induces CYP3A.
Methods: In this fixed-sequence arm of an open-label, phase 1 study (NCT04840888), healthy participants aged 18 to 65 years (n=15) received oral doses of 1.2mg MDZ alone (Day 1), CBZ twice daily (BID) alone (100mg Days 2-4; 200mg Days 5-7; 300mg Days 8-10 and 12-13), and 300mg CBZ BID plus 1.2mg MDZ (Days 11 and 14). Safety, tolerability, and pharmacokinetics were assessed.
Results: Overall, one participant (6.7%) experienced constipation due to treatment with CBZ plus MDZ on Day 11, which did not lead to discontinuation. One participant (6.7%) experienced urticaria (Days 12-13) and two participants (13.3%) experienced somnolence (Days 8-10) due to treatment with 300mg CBZ BID alone. All events were mild. For MDZ, the geometric mean (90% CI) ratio (versus 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 (0-12hr) of CBZ was 114 ug.h/mL on Day 11 and 105 ug.h/mL on Day 14.
Conclusion: The short dosing regimen for this CBZ induction study (up to Day 11) was well tolerated by healthy volunteers with no serious AEs or discontinuations. Steady state of CBZ was reached and the induction of CYP3A was complete at Day 11, supporting the use of the shorter CBZ dosing regimen for future CYP3A induction studies.
1. Bolleddula, J., Gopalakrishnan, S., Hu, P., Dong, J. & Venkatakrishnan, K. Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug-drug interaction studies. Clin. Transl. Sci. 15(9), 2075-2095 (2022). 2. Lutz, J.D. et al. Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 2: Prediction of Decreased Substrate Exposure After Rifabutin or Carbamazepine. Clin. Pharmacol. Ther. 104(6), 1191-1198 (2018).
