Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus

Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of midostaurin following multiple oral doses of midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100‐mg dose in patients with diabetes mellitus (n = 9–13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (Cmax and AUC0‐ẗ) of midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2‐fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%‐50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration‐time pattern as midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high‐fat meal was found to significantly increase the Cmax and AUC0–12 h of midostaurin by 1.5‐fold (P = .04) and 1.8‐fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment‐related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150‐mg/day dose level.