Repeated administration of 20 mg/kg ticagrelor reduced imatinib AUC0-24 by 24.8% and N-desmethyl imatinib AUC0-24 by 39.8% in rats after 14 days.
Does ticagrelor alter the pharmacokinetics and systemic exposure of imatinib in a rat model?
Repeated co-administration of high-dose ticagrelor significantly reduces systemic exposure to imatinib in rats, suggesting a potential drug-drug interaction that warrants clinical monitoring.
Estimación del efecto: 24.8% decrease in imatinib AUC0-24 with high-dose ticagrelor
Tasa de eventos absoluta: 54368.554% vs 72331.633%
valor p: p=0.024
Background: Patients with acute coronary syndrome (ACS) who also have chronic myelocytic leukemia (CML) or gastrointestinal stromal tumor (GIST) may receive a concurrent therapy of imatinib and ticagrelor. The absorption and transport of both drugs are influenced by organic anion transporting polypeptides (OATPs), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Furthermore, both are primarily metabolized by CYP3A4 enzymes. Thus, co-administration may lead to pharmacokinetic interactions. Therefore, this study aimed to investigate the effect of ticagrelor on imatinib pharmacokinetics in rats. Methods: A total of 30 Sprague-Dawley (SD) rats were randomly divided into three groups: a control group (imatinib 30 mg/kg), a low-dose experimental group (imatinib 30 mg/kg, ticagrelor 10 mg/kg), and a high-dose experimental group (imatinib 30 mg/kg, ticagrelor 20 mg/kg). All rats received the appropriate drugs once daily for 14 consecutive days. Venous blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on days 1 and 14, and the plasma was isolated. Pharmacokinetic parameters were calculated using DAS 2.0 software. Results: On day 1, no significant changes were observed in the pharmacokinetic parameters of either imatinib or any associated active metabolite, N-desmethyl imatinib. However, after 14 days, the high-dose experimental group showed a significant decrease in the area under the plasma concentration time curve for imatinib from 0 to 24 hours (area under the curve, AUC0-24) and from 0 to infinity (AUC0-∞). Similarly, the AUC0-24, AUC0-∞, and maximum concentration (Cmax) of N-desmethyl imatinib were also significantly reduced in the high-dose experimental group. In contrast, administering 10 mg/kg ticagrelor did not significantly affect the pharmacokinetics of imatinib or N-desmethyl imatinib. The trough plasma concentrations (Cmin) of both imatinib and N-desmethyl imatinib were not significantly altered in any group. Conclusions: Repeated administration of 20 mg/kg ticagrelor significantly inhibited imatinib absorption in rats. These results suggest that clinical symptoms and imatinib plasma concentration should be monitored when ticagrelor and imatinib are used concomitantly.
Guo et al. (Fri,) conducted a other in Sprague-Dawley rats aged 6-7 weeks (both sexes), administered imatinib ± ticagrelor to study pharmacokinetic interactions (n=30). Ticagrelor vs. Imatinib alone 30 mg/kg once daily was evaluated on Pharmacokinetic parameters of imatinib and N-desmethyl imatinib after 14 days of administration including AUC0-24, AUC0-∞, Tmax, Cmax, Vz/F (24.8% decrease in imatinib AUC0-24 with high-dose ticagrelor, p=0.024). Repeated administration of 20 mg/kg ticagrelor reduced imatinib AUC0-24 by 24.8% and N-desmethyl imatinib AUC0-24 by 39.8% in rats after 14 days.