The effect of carbamazepine, a strong CYP3A inducer, on the pharmacokinetics of zongertinib in healthy male volunteers

Abstract Introduction Zongertinib (BI 1810631) is a potent, selective, and epidermal growth factor receptor (EGFR) wild‐type sparing human epidermal growth factor receptor 2 (HER2) inhibitor. Based on in vitro data, the oxidative hepatic metabolism of zongertinib is principally driven by cytochrome P450 (CYP) 3A4/5. Therefore, zongertinib may be affected by strong CYP3A inducers, like carbamazepine. Objective This study aimed to investigate the effect of multiple oral doses of carbamazepine on the pharmacokinetics of a single oral dose of zongertinib in healthy male subjects. Methods This open‐label, two‐period, fixed‐sequence clinical drug–drug interaction study examined the pharmacokinetics of a single 60‐mg oral dose of zongertinib in the absence or presence of multiple oral doses of carbamazepine. The extent of drug–drug interaction was estimated using the adjusted geometric mean ratios (and 90% confidence intervals [CIs]) for the test treatment (zongertinib in the presence of carbamazepine) versus the reference treatment (zongertinib alone) for areas under the plasma concentration–time curve from time 0 to infinity and to the last quantifiable time point (AUC 0–∞ , AUC 0–tz ) and maximum measured plasma concentration ( C max ). Results Sixteen subjects (all Caucasian males) received zongertinib alone in Study Period 1, and 15 of them received both zongertinib and carbamazepine in Study Period 2. Upon co‐administration with carbamazepine in Study Period 2, AUC 0–∞ and AUC 0–tz of zongertinib were both reduced to 36.5% (90% CI: 32.0%–41.6% for AUC 0–∞ and 31.9%–41.7% for AUC 0–tz ). The C max of zongertinib was reduced to 56.4% (90% CI: 45.1%–70.6%). Conclusion Zongertinib exposure was reduced by 63.5% when coadministered with the strong CYP3A inducer, carbamazepine.