Radotinib is a second-generation tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML). This study was performed to charaterize the population pharmacokinetics (PPK) of radotinib, identify factors contributing to PK variabilities and explore alternative dosing regimens, using a total of 640 plasma concentration-time points from 23 healthy volunteers (HVs) and 24 CML patients. HVs received a single, oral dose of radotinib 400 mg, and CML patients the repeated doses of 300 mg twice daily. The PPK of radotinib using nonlinear mixed-effects modeling was best described by a two-compartment model with first-order absorption via transit compartments and first-order elimination reflecting circadian rhythmic effect. Apparent clearance (CL/F) was 39.2% lower in CML patients (23.0 L/h) than in HVs (37.9 L/h), corresponding to a longer terminal half-life (28.8 h vs. 17.5 h). Age was inversely related to the apparent volume of distribution in central compartment (Vc/F) with an estimated decrease of 0.0129 L/year. Based on the PPK model, the feasibility of extending the current twice-daily regimen was assessed using Monte Carlo simulations. A once-daily regimen of 400 mg yielded 36% lower exposure than that of current regimen, which will likely improve the tolerability of radotinib. This PPK model provides a basis for a precision therapy of radotinib for the treatment of CML patients.