Zongertinib

Zongertinib is a kinase inhibitor of human epidermal growth factor receptor 2 (HER2). In vitro, zongertinib inhibited phosphorylation of HER2, downstream signaling of HER2 (phosphorylation of ERK), and proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations. In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC harboring HER2 tyrosine kinase domain activating mutations.

The exposure-response relationship and time-course of pharmacodynamic response of zongertinib have not been fully characterized.

Cardiac Electrophysiology

At 2.6 times the mean maximal concentration provided by the recommended dose of 120 mg, a mean increase in the QTc interval >20 ms was not observed.

Zongertinib pharmacokinetics were observed at steady state in patients with advanced or metastatic solid tumors with HER2 aberrations at the approved recommended dosage and are presented as geometric mean (CV%), unless otherwise specified.

Zongertinib maximum concentration (C_max,ss) is 3.0 (37%) µmol/L and the total systemic exposure (AUC) is 34 (34%) µmol*h/L following zongertinib 120 mg orally daily. Zongertinib C_max and AUC increase in an approximately dose proportional manner across the dose range of 60 mg (0.5 times the approved recommended dosage) to 360 mg (3 times the approved recommended dosage). Zongertinib accumulation is approximately 1.5-fold for AUC and 1.3-fold for C_max at the approved recommended dosage. Steady state is achieved within 2.5 days.

Absorption

Zongertinib median (min, max) time to maximum plasma concentration (T_max) is approximately 2 hours (min, max: 2, 6 hours). Zongertinib absolute oral bioavailability is 76%.

Effect of Food

No clinically significant differences in zongertinib C_max and AUC were observed following administration of a single 240 mg dose (2 times the approved recommended dose) with a high-fat meal (approximately 1,000 calories, approximately 50% fat).

Distribution

Zongertinib plasma protein binding is >99%. The apparent (oral) volume of distribution is 118 L (29%).

Elimination

Zongertinib effective half-life is 12 hours (21%) with an apparent (oral) clearance of 115 mL/min (31%).

Metabolism

Based on in vitro metabolite profiling, CYP-mediated oxidation pathways represent 48% to 62% (mainly CYP3A4 and CYP3A5), glucuronidation 13% to 25% (mainly UGT1A4), and glutathione conjugation 13% to 26% of total hepatic metabolism. Unchanged zongertinib represented the majority (75%) of total radioactivity in plasma.

Excretion

After a single oral dose of radiolabeled zongertinib 60 mg to healthy participants, approximately 93% of the dose was recovered in feces (31% unchanged) and 1.3% in urine (0.2% unchanged).

Specific Populations

The apparent volume of distribution and clearance of zongertinib increase with increasing body weight (34 to 122 kg).

No clinically significant differences in the pharmacokinetics of zongertinib were observed based on age (30 to 88 years), sex, race (36% White, 49% Asian, 1.3% Black/African American), mild renal impairment (eGFR 60 to <90 mL/min) or mild hepatic impairment (AST > ULN and total bilirubin ≤ ULN; or total bilirubin >1 to 1.5× ULN and any AST). The effect of moderate renal impairment (eGFR 30 to <60 mL/min), severe renal impairment (eGFR 15 to <30 mL/min), end-stage renal disease (eGFR <15 mL/min), moderate hepatic impairment (total bilirubin >1.5 to 3× ULN and any AST) or severe hepatic impairment (total bilirubin >3× ULN and any AST) on the pharmacokinetics of zongertinib have not been studied.

Drug Interaction Studies

CYP3A Inducers

Zongertinib AUC decreased by 63% and C_max decreased by 43% following concomitant use of carbamazepine (strong CYP3A inducer) 600 mg once daily for 7 days. The effect of concomitant use of moderate CYP3A inducers on zongertinib C_max and AUC are unknown.

BCRP Substrates

Rosuvastatin (BCRP substrate) C_max increased by 3-fold and AUC by 2.3-fold following concomitant use of a single dose of zongertinib 120 mg daily for 12 days.

Other Drugs

No clinically significant differences in zongertinib pharmacokinetics were observed when used concomitantly with strong CYP3A, P-gp, BCRP inhibitors and rabeprazole (proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following were observed when used concomitantly with zongertinib: midazolam (a CYP3A substrate), dabigatran (a P-gp substrate), metformin (a OCT2 and MATE1/2-K substrate), or repaglinide (a sensitive CYP2C8 substrate).

In a 4-week repeat-dose toxicology study in dogs, oral administration of zongertinib induced lesions of the oral mucosa (hard palate, buccal mucosa, tongue, lips) at doses ≥10 mg/kg/day (≥0.3 times the human exposure based on AUC at the recommended dose), which correlated with histologic erosion/ulcer and impaired food consumption. These findings were not present following a 4-week recovery period.