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

Abstract

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.

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

“…The non-linear pharmacokinetics of CGP62221 follows the same pattern as that of midostaurin, whereas the second metabolite, CGP52421, rises over time until reaching steady-state concentrations after one month of daily treatment (33)(34)(35)(36)(37). Our data show that CGP52421 is less effective in producing growth inhibition and apoptosis in neoplastic MC when compared to midostaurin.…”

“…or 75 mg t.i.d. ), day-28 plasma exposure as assessed by area under the plasma-concentration time curve (AUC), for CGP62221 was slightly higher than that for midostaurin, whereas for CGP52421, the AUC52421/AUCmidostaurin ratio was greater than 5 (37).…”

“…A remarkable phenomenon is that even in patients who have resistant disease or relapse, mediator-related symptoms improve or disappear during therapy (30). treatment, followed by a significant decrease, before reaching a stable plateau after 3-4 weeks (33)(34)(35)(36)(37). The drug has two active metabolites (Supplementary Figure S1), which result from cytochrome CYP3A4-mediated oxidation of the parent-drug (36,37).…”

Proteomic and genomic integration identifies kinase and differentiation determinants of kinase inhibitor sensitivity in leukemia cells

“…Consistently with this hypothesis, cell viability analysis as a function of treatment with kinase inhibitors showed that CDs+ cases were more sensitive than CDs-to MEKi (at 10, 100 and 1,000nM), FLT3/PKCi (1 and 10μM) and PAKi (1μM) (Figure 1c). These concentrations are physiologically relevant for MEKi and FLT3/PKCi 8,9 .…”

Protein kinase C βII in diabetic complications: survey of structural, biological and computational studies

“…Some of the reported PKC inhibitors are mentioned in Table 1, viz. Midostaurin (PKC412, CGS41251, N-benzoyl staurosporine), UCN-01 (KW-2401, NSC-638850), Lestaurtinib (CEP-701, KT-5555), Ro-31 --8220 and Go6976 [41][42][43][44][45][46].…”