Background: Gilteritinib, also known as ASP2215, is a selective FLT3 inhibitor in development for the treatment of acute myeloid leukemia (AML). In ongoing trials, gilteritinib has demonstrated antileukemic activity and has been well tolerated in FLT3-mutation positive subjects with relapsed/refractory (R/R) AML. Methods: Gilteritinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in adult subjects ( ≥ 18 years) with R/R AML in an ongoing phase 1/2 dose-escalation/dose-expansion study (NCT02014558). Gilteritinib was administered once daily (20-450 mg) and blood samples were collected for safety, PK, and PK/PD assessments. Results: As of October 31, 2015, data were available from 252 subjects (n = 23, dose escalation; n = 229, dose expansion) for preliminary PK and PK/PD analyses. Gilteritinib PK was generally dose proportional from 20-450 mg with a median time to maximal concentration of 2–6 hr and a median half-life ~45–159 hr. Increased efficacy was observed in subjects with gilteritinib steady-state trough concentrations ≥ 100 ng/mL, exposure levels that can be achieved in patients dosed at 120 mg gilteritinib once daily. Although ΔQTcF is positively correlated to gilteritinib concentration, the preliminary model-averaged predicted median maximal ΔQTcF (5.8 msec) and 1-sided upper 95% CI (8.7 msec) were less than 10 msec at the mean exposure associated with the 120 mg therapeutic dose. Furthermore, a low incidence of subjects (4.1%) had a maximum post-baseline QTcF interval > 500 msec. While concentration-related increases in ΔCK and ΔAST were observed, < 10% of subjects experienced a ≥ Grade 3 increase in ΔCK or ΔAST. Conclusions: The gilteritinib PK and safety profile support QD oral administration. At 120 mg QD, gilteritinib concentrations associated with increased efficacy are readily achieved and substantial QTc prolongation is not anticipated. Concentration-related increases in ΔCK and ΔAST did not translate to high frequency of incidences ≥ Grade 3 and are clinically manageable. Clinical trial information: NCT02014558