Effect of dosing interval on the pharmacokinetic interaction between montmorillonite powder and pyrotinib in rats.

AIMS: Montmorillonite powder (MP) can adsorb pyrotinib and reduce its bioavailability. This study investigated the effects of different dosing intervals on the pharmacokinetic interaction between MP and pyrotinib in rats. METHODS: Eighteen male Sprague-Dawley rats were randomly assigned to three groups (n = 6/group): Control (pyrotinib alone), 0.5-h interval (MP given 0.5 h after pyrotinib), and 2.0-h interval (MP given 2.0 h after pyrotinib). Pyrotinib (10 mg/kg) was orally administered to all rats, followed by MP (240 mg/kg) or water (control) at designated time points. Blood samples were collected up to 24 h post-dose. Plasma pyrotinib concentrations were determined by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated using WinNonlin. RESULTS: The 0.5-h interval group showed substantially reduced pyrotinib exposure, with area under the curve (AUC) from time zero to last time point (AUClast) and AUC from time zero to infinity (AUCinf) decreasing by 31.2% and 31.3%, respectively, indicating statistically significant reductions (90% CIs <1.0). C max reduction was 20.7%, which was not statistically significant (90% CI crossed 1.0). For the 2.0-h interval group, all GMRs were close to unity, but the wide 90% CIs (69.1%-137.6%) could not rule out a clinically meaningful impact. CONCLUSION: In rats, MP administration at an insufficient dosing interval markedly compromises pyrotinib systemic exposure, whereas adequate temporal separation largely mitigates this interaction. These findings underscore the urgent need for dedicated clinical pharmacokinetic studies to define the optimal dosing interval in humans and to minimize the risk of subtherapeutic pyrotinib exposure in clinical practice.