Effect of diosmectite on the pharmacokinetics of osimertinib in rats

Diosmectite is commonly used in clinical practice to manage osimertinib-induced diarrhea, but its impact on osimertinib absorption remains unclear. Eighteen male Sprague–Dawley rats were randomly assigned to three groups (n=6/group): control (osimertinib alone), co-administration (osimertinib immediately followed by diosmectite), and delayed-administration (diosmectite 0.5-hour after osimertinib). Blood samples were collected from the jugular vein at predetermined time points (0.25, 0.5, 1, 2, 4, 6, 8, and 24 h) after osimertinib administration. Plasma osimertinib concentrations were measured using a fully validated LC-MS/MS. Pharmacokinetic parameters were calculated using noncompartmental analysis. Compared with controls, co-administration reduced Cmax by 91.6% (84.8 ± 19.4 vs. 7.14 ± 2.15 ng·mL-1, P<0.05) and AUClast by 94.4% (670 ± 353 vs. 37.8 ± 9.7 h·ng·mL-1, P<0.05). Delayed-administration reduced Cmax by 38.0% (84.8 ± 19.4 vs. 52.6 ± 22.8 ng·mL-1, P<0.05) and AUClast by 66.3%(670 ± 353 vs. 226 ± 88 h·ng·mL-1, P<0.05). Diosmectite markedly reduces the oral absorption of osimertinib in rats. Delaying diosmectite by 0.5-hour partially but incompletely restores absorption. Clinical studies are needed to further verify this interaction.