Hélène Pereira, Stefan Wölke, Behbood Sadrolhefazi, Habib Esmaeili, Sven Wind, Guanfa Gan, Fabian Müller, David Minich, Kerstin Bader, Rolf Grempler, Yeuk Ki Law, Philipp M Roessner
{"title":"健康男性受试者在进食和禁食条件下口服her2选择性酪氨酸激酶抑制剂宗尔替尼的相对生物利用度：来自两项随机、开放标签、交叉研究的结果","authors":"Hélène Pereira, Stefan Wölke, Behbood Sadrolhefazi, Habib Esmaeili, Sven Wind, Guanfa Gan, Fabian Müller, David Minich, Kerstin Bader, Rolf Grempler, Yeuk Ki Law, Philipp M Roessner","doi":"10.1021/acs.molpharmaceut.5c00832","DOIUrl":null,"url":null,"abstract":"<p><p>Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is mutated in various solid tumors. Zongertinib (BI 1810631) is a novel, orally administered, HER2-specific tyrosine kinase inhibitor that spares the epidermal growth factor receptor (EGFR), limiting EGFR-related adverse events. Zongertinib has recently received accelerated approval in the United States and China for patients with advanced, previously treated, <i>HER2</i> mutant NSCLC. Two Phase I open-label crossover studies evaluated the effect of a high-fat, high-calorie meal on zongertinib bioavailability at two doses: 30 mg (NCT05380947) and 240 mg (NCT06075277). Healthy male participants were randomized to treatment sequences in which they received single doses of zongertinib (spray-dried dispersion formulations) under fed and fasted conditions. The washout interval was ≥14 days. The primary end points were the area under the concentration-time curve of zongertinib in plasma over the time from 0 to the last quantifiable data point (AUC<sub>0-tz</sub>), and the maximum measured concentration of zongertinib in plasma (<i>C</i><sub>max</sub>). In NCT05380947, 13 participants received 30 mg of zongertinib. The ratios of adjusted geometric means demonstrated lower AUC<sub>0-tz</sub> and <i>C</i><sub>max</sub>, under fed (<i>n</i> = 9) versus fasted (<i>n</i> = 12) conditions (fed/fasted, % [90% CI]: AUC<sub>0-tz</sub>, 74.2% [67.6-81.6]; <i>C</i><sub>max</sub>, 53.5% [40.5-70.8]). In NCT06075277, the ratios of adjusted geometric means for AUC<sub>0-tz</sub> and <i>C</i><sub>max</sub> were ∼26% higher under fed versus fasted conditions (fed/fasted, % [90% CI]: AUC<sub>0-tz</sub>, 126.6% [112.1-143.1]; <i>C</i><sub>max</sub>, 126.1% [106.3-149.6]). In both studies, median <i>t</i><sub>max</sub> was delayed (NCT05380947/NCT06075277) under fed (3/4 h) versus fasted (1.5/2 h) conditions. Zongertinib demonstrated good bioavailability in healthy participants. A small dose-dependent food effect was observed.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Relative Bioavailability of Zongertinib, an Orally Administered HER2-Selective Tyrosine Kinase Inhibitor, under Fed and Fasted Conditions in Healthy Male Participants: Results from Two Randomized, Open-Label, Crossover Studies.\",\"authors\":\"Hélène Pereira, Stefan Wölke, Behbood Sadrolhefazi, Habib Esmaeili, Sven Wind, Guanfa Gan, Fabian Müller, David Minich, Kerstin Bader, Rolf Grempler, Yeuk Ki Law, Philipp M Roessner\",\"doi\":\"10.1021/acs.molpharmaceut.5c00832\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is mutated in various solid tumors. Zongertinib (BI 1810631) is a novel, orally administered, HER2-specific tyrosine kinase inhibitor that spares the epidermal growth factor receptor (EGFR), limiting EGFR-related adverse events. Zongertinib has recently received accelerated approval in the United States and China for patients with advanced, previously treated, <i>HER2</i> mutant NSCLC. Two Phase I open-label crossover studies evaluated the effect of a high-fat, high-calorie meal on zongertinib bioavailability at two doses: 30 mg (NCT05380947) and 240 mg (NCT06075277). Healthy male participants were randomized to treatment sequences in which they received single doses of zongertinib (spray-dried dispersion formulations) under fed and fasted conditions. The washout interval was ≥14 days. The primary end points were the area under the concentration-time curve of zongertinib in plasma over the time from 0 to the last quantifiable data point (AUC<sub>0-tz</sub>), and the maximum measured concentration of zongertinib in plasma (<i>C</i><sub>max</sub>). In NCT05380947, 13 participants received 30 mg of zongertinib. The ratios of adjusted geometric means demonstrated lower AUC<sub>0-tz</sub> and <i>C</i><sub>max</sub>, under fed (<i>n</i> = 9) versus fasted (<i>n</i> = 12) conditions (fed/fasted, % [90% CI]: AUC<sub>0-tz</sub>, 74.2% [67.6-81.6]; <i>C</i><sub>max</sub>, 53.5% [40.5-70.8]). In NCT06075277, the ratios of adjusted geometric means for AUC<sub>0-tz</sub> and <i>C</i><sub>max</sub> were ∼26% higher under fed versus fasted conditions (fed/fasted, % [90% CI]: AUC<sub>0-tz</sub>, 126.6% [112.1-143.1]; <i>C</i><sub>max</sub>, 126.1% [106.3-149.6]). In both studies, median <i>t</i><sub>max</sub> was delayed (NCT05380947/NCT06075277) under fed (3/4 h) versus fasted (1.5/2 h) conditions. Zongertinib demonstrated good bioavailability in healthy participants. 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Relative Bioavailability of Zongertinib, an Orally Administered HER2-Selective Tyrosine Kinase Inhibitor, under Fed and Fasted Conditions in Healthy Male Participants: Results from Two Randomized, Open-Label, Crossover Studies.
Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is mutated in various solid tumors. Zongertinib (BI 1810631) is a novel, orally administered, HER2-specific tyrosine kinase inhibitor that spares the epidermal growth factor receptor (EGFR), limiting EGFR-related adverse events. Zongertinib has recently received accelerated approval in the United States and China for patients with advanced, previously treated, HER2 mutant NSCLC. Two Phase I open-label crossover studies evaluated the effect of a high-fat, high-calorie meal on zongertinib bioavailability at two doses: 30 mg (NCT05380947) and 240 mg (NCT06075277). Healthy male participants were randomized to treatment sequences in which they received single doses of zongertinib (spray-dried dispersion formulations) under fed and fasted conditions. The washout interval was ≥14 days. The primary end points were the area under the concentration-time curve of zongertinib in plasma over the time from 0 to the last quantifiable data point (AUC0-tz), and the maximum measured concentration of zongertinib in plasma (Cmax). In NCT05380947, 13 participants received 30 mg of zongertinib. The ratios of adjusted geometric means demonstrated lower AUC0-tz and Cmax, under fed (n = 9) versus fasted (n = 12) conditions (fed/fasted, % [90% CI]: AUC0-tz, 74.2% [67.6-81.6]; Cmax, 53.5% [40.5-70.8]). In NCT06075277, the ratios of adjusted geometric means for AUC0-tz and Cmax were ∼26% higher under fed versus fasted conditions (fed/fasted, % [90% CI]: AUC0-tz, 126.6% [112.1-143.1]; Cmax, 126.1% [106.3-149.6]). In both studies, median tmax was delayed (NCT05380947/NCT06075277) under fed (3/4 h) versus fasted (1.5/2 h) conditions. Zongertinib demonstrated good bioavailability in healthy participants. A small dose-dependent food effect was observed.
期刊介绍：
Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development.
Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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