The Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of a Single Oral Dose of Zongertinib in Healthy Male Volunteers

ABSTRACT Introduction Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing wild‐type epidermal growth factor receptor (EGFR), thereby minimizing associated toxicities. Oxidative hepatic metabolism of zongertinib in vitro is principally driven by cytochrome P450 (CYP) 3A. It is necessary, therefore, to assess the effect of a strong CYP3A inhibitor on the pharmacokinetics of zongertinib in humans. Objective This study investigated the effect of multiple oral doses of the strong CYP3A inhibitor and regulatory‐recommended probe inhibitor of P‐glycoprotein (P‐gp), itraconazole, on the pharmacokinetics of a single dose of zongertinib in healthy male participants. Methods This open‐label, two‐period, fixed‐sequence, clinical drug–drug interaction study assessed the pharmacokinetics of a 15 mg oral dose of zongertinib in the absence and presence of multiple oral doses of itraconazole. The extent of drug–drug interaction was estimated using the adjusted geometric mean (gMean) ratios (90% confidence intervals [CIs]) for the test (T) treatment (zongertinib and itraconazole) vs. the reference (R) treatment (zongertinib alone). Primary endpoints were the area under the plasma concentration–time curve from time 0 to infinity (AUC 0–∞ ) and the maximum measured plasma concentration (C max ) of zongertinib. The secondary pharmacokinetic endpoint was AUC for zongertinib from time 0 to the last quantifiable time point (AUC 0–tz ). Results Sixteen participants received zongertinib alone (Period 1, R), followed by co‐administration with itraconazole (Period 2, T). In terms of zongertinib exposure, the gMean ratio of T to R was 141.2% (90% CI: 126.3–157.7%) for AUC 0–∞ , 142.8% (90% CI: 126.0–161.9%) for AUC 0–tz , and 126.9% (90% CI: 106.6–151.0%) for C max . Conclusion Co‐administration with itraconazole resulted in a mild increase in total exposure to zongertinib that was not considered clinically relevant given its wide therapeutic window. These data indicate that the approved 120 mg dose of zongertinib can be administered without dose adjustment in combination with CYP3A/P‐gp inhibitors.