Background Dirozalkib is a novel anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with an intended indication for ALK-positive advanced non-small cell lung cancer (NSCLC). Given that the solubility of Dirozalkib is pH-dependent, this study was conducted to evaluate the effect of the acid-reducing agent, esomeprazole magnesium (EMZ-Mg) enteric-coated tablets, on the pharmacokinetics of Dirozalkib. Methods In this open-label, single center, two-treatment, single-sequence clinical trial, 24 healthy adults were enrolled. Participants received a single oral dose of 500 mg Dirozalkib on Day 1 and 16. Oral EMZ-Mg enteric-coated tablet (40 mg) were administered once daily from Days 11 to 16. Blood samples were collected, and plasma concentrations of Dirozalkib and its primary metabolite XZP-5089 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were derived via noncompartmental analysis, and safety was assessed throughout the study. Results All 24 participants completed both treatment periods. Coadministration with EMZ-Mg enteric-coated tablet resulted in a reduction of the geometric mean maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0 − t), and area under the curve from time zero to infinity (AUC0−∞) of Dirozalkib by about 27.0%, 12.0%, and 12.0%, respectively. The median time to maximum (Tmax) was prolonged from 3.0 h to 4.0 h (P = 0.005). The geometric mean ratios (GMRs) (coadministration/monotherapy) with their 90% confidence intervals (CIs) for Dirozalkib were: Cmax, 73.28% (64.18%-83.68%), AUC0 − t, 87.97% (81.36%-95.12%) and AUC0–∞: 88.12% (81.53%-95.24%). Similar effects were observed for the primary metabolite XZP-5089. Treatment-related adverse events (TRAEs) were reported by 20 participants (83.3%) following Dirozalkib monotherapy and 17 participants (70.8%) following coadministration, all of which were Grade 1 to 3 in severity. Conclusion The co-administration of Dirozalkib and EMZ-Mg enteric-coated tablet slightly reduced the exposure of Dirozalkib and prolonged the peak time. Clinical trial registration The study was registered at <a href="https://clinicaltrials.gov">https://clinicaltrials.gov</a> (NCT05586568).

Presence of drug-drug interactions between esomeprazole and an ALK tyrosine kinase inhibitor (Dirozalkib)

期刊论文
发表日期：

2025年12月5日

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Lin Fang,
Xin Jiang,
Kexiu Song,
Ping Shi,
Li Wang,
Lingmei Xu,
Xianghui Duan,
Fei Liu,
Feifei Sun,
Rongxin Ban,
Yaping Ma,
Chenjing Wang,
Yu Cao

摘要

Background

Dirozalkib is a novel anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with an intended indication for ALK-positive advanced non-small cell lung cancer (NSCLC). Given that the solubility of Dirozalkib is pH-dependent, this study was conducted to evaluate the effect of the acid-reducing agent, esomeprazole magnesium (EMZ-Mg) enteric-coated tablets, on the pharmacokinetics of Dirozalkib.

Methods

In this open-label, single center, two-treatment, single-sequence clinical trial, 24 healthy adults were enrolled. Participants received a single oral dose of 500 mg Dirozalkib on Day 1 and 16. Oral EMZ-Mg enteric-coated tablet (40 mg) were administered once daily from Days 11 to 16. Blood samples were collected, and plasma concentrations of Dirozalkib and its primary metabolite XZP-5089 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were derived via noncompartmental analysis, and safety was assessed throughout the study.

Results

All 24 participants completed both treatment periods. Coadministration with EMZ-Mg enteric-coated tablet resulted in a reduction of the geometric mean maximum plasma concentration (C_max), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC_0 − t), and area under the curve from time zero to infinity (AUC_0−∞) of Dirozalkib by about 27.0%, 12.0%, and 12.0%, respectively. The median time to maximum (T_max) was prolonged from 3.0 h to 4.0 h (P = 0.005). The geometric mean ratios (GMRs) (coadministration/monotherapy) with their 90% confidence intervals (CIs) for Dirozalkib were: C_max, 73.28% (64.18%-83.68%), AUC_0 − t, 87.97% (81.36%-95.12%) and AUC_0–∞: 88.12% (81.53%-95.24%). Similar effects were observed for the primary metabolite XZP-5089. Treatment-related adverse events (TRAEs) were reported by 20 participants (83.3%) following Dirozalkib monotherapy and 17 participants (70.8%) following coadministration, all of which were Grade 1 to 3 in severity.

Conclusion

The co-administration of Dirozalkib and EMZ-Mg enteric-coated tablet slightly reduced the exposure of Dirozalkib and prolonged the peak time.

Clinical trial registration

The study was registered at https://clinicaltrials.gov (NCT05586568).