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 (C(max) and AUC(0-tau)) 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 C(max) and AUC(0-12 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.