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.

Keywords: carbamazepine; drug interaction; enzyme induction; non‐small cell lung cancer; pharmacokinetics; tyrosine kinase inhibitor; zongertinib.

FIGURE 1

Study design. This open‐label, two‐period, fixed‐sequence, drug–drug interaction study in healthy male subjects aimed to compare the test treatment (T) in Period 2 to the reference treatment (R) in Period 1. R was a single oral dose of zongertinib 60 mg film‐coated tablet given alone on Day 1 of Period 1. T was a single oral dose of zongertinib 60 mg administered on Day 1 together with multiple oral doses of carbamazepine from Day −18 to Day 6 of Study Period 2. Day −18 of Period 2 is the day after Day 8 of Period 1. Carbamazepine was dosed at 200 mg QD for 4 days (Day −18 to Day −15), titrated to 400 mg QD for 7 days (Day −14 to Day −8), and then to a final dose of 600 mg QD for 13 days (Day −7 to Day 6). Blood samples were collected at various time points as indicated in the figure for assessment of zongertinib PK, carbamazepine PK, and 4βHC plasma concentrations. Multiple 24‐h urine collections were planned in Period 2 for the quantification of 6βHC to cortisol ratios (6βCR). 4βHC, 4β‐OH‐cholesterol; 6βCR, 6βHC to cortisol ratio; 6βHC, 6β‐OH‐cholesterol; EoS, end of study; PK, pharmacokinetic; QD, once daily; SCR, screening.

FIGURE 2

Change in CYP3A induction biomarkers over time (N = 15). Mean (± SD) of 6βCR in urine and 4βHC in plasma over time in Study Period 2 with multiple oral doses of carbamazepine and a single dose of zongertinib in 15 healthy male subjects. The time of zongertinib administration is defined as hour 0. Upper panels (A, B) show 6βCR, and lower panels (C, D) depict 4βHC. Left panels (A, C) show original values prior to baseline correction over time, and right panels (B, D) show percentage change from baseline (PCB) over time. 4βHC, 4β‐OH‐cholesterol; 6βCR, 6β‐OH‐cortisol to cortisol ratio; CYP3A, cytochrome P450 3A; PCB, percent change from baseline calculated by (value‐baseline)/baseline × 100%; SD, standard deviation.

FIGURE 3

Mean plasma concentration‐time profiles of zongertinib after a single 60‐mg oral dose of zongertinib in the absence (R) and presence (T) of multiple doses of carbamazepine. Linear and semilogarithmic scale (mean ± SD). Only higher SD whiskers are displayed for R treatment, and lower SD whiskers are displayed for T treatment for clarity for both linear and semilogarithmic plots. Whiskers of SD reaching negative values were not displayed in the semilogarithmic plot. R: zongertinib 60 mg at Day 1 of Period 1. T: zongertinib 60 mg at Day 1 of Period 2 + carbamazepine 200 mg QD from Day −18 to Day −15, titrated to 400 mg QD from Day −14 to Day −8, to 600 mg QD from Day −7 to Day 6. CBZ, carbamazepine; QD, once daily; SD, standard deviation.

FIGURE 4

Relative bioavailability of a single oral dose of 60 mg zongertinib coadministered with multiple oral doses of carbamazepine (T; N = 15) relative to a single oral dose of 60 mg zongertinib alone (R; N = 16). Adjusted gMean ratios and 90% confidence intervals. R: zongertinib 60 mg at Day 1 of Period 1. T: zongertinib 60 mg at Day 1 of Period 2 + carbamazepine 200 mg once daily from Day −18 to Day −15, titrated to 400 mg once daily from Day −14 to Day −8, to 600 mg once daily from Day −7 to Day 6. AUC_0–∞, area under the plasma concentration‐time curve over the time interval from 0 to infinity; AUC_0–tz, area under the plasma concentration–time curve over the time interval from 0 to the last quantifiable data point; C _max, maximum measured concentration of the analyte in plasma; gMean, geometric mean; R, reference; T, test.