Midostaurin (Rydapt)
(Novartis) Time to Tmax between 1-3 h post dose in fasted state;
following 50 mg oral dose, mean Cmax (total circulating radioactivity, unchanged midostaurin, and metabolites CGP52421 and CGP62221)=2160 ng/mL, 1240 ng/mL, 328 ng/mL and 562 ng/mL, respectively;
mean AUC (0-infinity) (total circulating radioactivity, unchanged midostaurin, and metabolites CGP52421 and CGP62221) =165 x 103 ng Eq*h/mL, 15.7 x 103 ng*h/mL, 146 x 103 ng*h/mL, and 27.1 x 103 ng*h/mL, respectively;
high oral absorption rate following 50 mg dose (190);
rat and dog: bioavailability low to moderate (9.3-48.5%); human oral bioavailability low to moderate (190);
Vd =95.2L (parent drug and metabolites distributed in plasma) Metabolized by hepatic CYP3A4
(Yin et al.,2008);
CYP3A4 inhibitors may increase exposure to midostaurin and active metabolites 50 mg orally twice daily;
>99.9% binding (AAG) One case reported of interstitial lung disease while on midostaurin therapy post allogeneic stem cell transplant (191); in phase III trial, 8% of midostaurin-treated patients had grade 3-5 pneumonitis or radiographic pulmonary opacities (192)