Nonclinical and Clinical Assessments of an Optimized Tablet Formulation of the Novel HER2-Selective Tyrosine Kinase Inhibitor Zongertinib: Focus on Relative Bioavailability and Impact of Variation of Gastric pH

Wölke S, Sadrolhefazi B, Esmaeili H, Wind S, Blattner SM, Gan G, Qiang D, Schirmer A, Müller F (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Molecular Pharmaceutics American Chemical Society

Book Volume: 22

Pages Range: 6522-6530

Journal Issue: 11

DOI: 10.1021/acs.molpharmaceut.5c00831

Abstract

Zongertinib (BI 1810631), a novel orally administered HER2-specific tyrosine kinase inhibitor, has recently received accelerated approval in the United States and China for patients with advanced, previously treated HER2 mutant NSCLC. This multifaceted analysis assessed the influence of gastric pH variation on the pharmacokinetics of conventional and spray-dried dispersion (SDD) formulations of zongertinib. The influence of gastric pH on zongertinib pharmacokinetics was evaluated in male beagles. Increased gastric pH substantially reduced absorption of zongertinib as a Natrosol suspension. At low gastric pH, the SDD formulation provided improved exposure and reduced variability compared with a conventional formulation. We then evaluated the in vitro release and bioaccessibility of conventional and SDD tablet formulations of zongertinib with the tiny-TIM gastrointestinal system. Bioaccessibility was similar between the two formulations under simulated fasted conditions; however, under simulated fasted conditions with a proton pump inhibitor, the conventional formulation showed reduced bioaccessibility versus SDD. In a randomized, open-label crossover study, fasted healthy human male participants received 30 mg zongertinib as a conventional tablet formulation, an SDD tablet formulation, and as an SDD tablet formulation after multiple doses of rabeprazole 40 mg. The primary pharmacokinetic end points were area under the plasma concentration–time curve from time 0 to the last quantifiable point (AUC0-tz) and maximum plasma concentration (Cmax) of zongertinib. Cmaxand AUC0-tzwere ∼39% and ∼35% higher, respectively, with the SDD versus the conventional formulation. Geometric mean Cmaxand AUC0-tzwere similar after treatment with zongertinib SDD with and without rabeprazole. Zongertinib SDD formulation showed good bioavailability irrespective of pH, supporting further clinical development.

Involved external institutions

Boehringer Ingelheim Pharma GmbH & Co. KG DE Germany (DE) Staburo GmbH DE Germany (DE)

How to cite

APA:

Wölke, S., Sadrolhefazi, B., Esmaeili, H., Wind, S., Blattner, S.M., Gan, G.,... Müller, F. (2025). Nonclinical and Clinical Assessments of an Optimized Tablet Formulation of the Novel HER2-Selective Tyrosine Kinase Inhibitor Zongertinib: Focus on Relative Bioavailability and Impact of Variation of Gastric pH. Molecular Pharmaceutics, 22(11), 6522-6530. https://doi.org/10.1021/acs.molpharmaceut.5c00831

MLA:

Wölke, Stefan, et al. "Nonclinical and Clinical Assessments of an Optimized Tablet Formulation of the Novel HER2-Selective Tyrosine Kinase Inhibitor Zongertinib: Focus on Relative Bioavailability and Impact of Variation of Gastric pH." Molecular Pharmaceutics 22.11 (2025): 6522-6530.

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