(M1030-05-29) Evaluation of Pharmacokinetic Characteristics and the Food Effect of Radotinib in Healthy Volunteers

Purpose: Radotinib, a second-generation tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia (CML), is approved as a dosing regimen of 300 mg twice daily on an empty stomach. This study aimed to evaluate the pharmacokinetic (PK) characteristics of radotinib, and to assess the effect of food on the absorption of radotinib in healthy volunteers.

Methods: Eligible healthy participants were randomized to one of two treatment sequences in a crossover manner, each consisting of two periods separated by a washout period of 14 days. In each period, participants received a single oral dose of radotinib 400 mg either on an empty stomach or 30 minutes after consuming a standard meal consisting of 700-900 kcal with 20-35% of calories derived from fat. Blood samples were collected from each participant’s arm vein pre-dose, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 32, 48 and 72 hours post-dose . The plasma concentrations (Cp) of radotinib were quantified using a validated liquid chromatographic method with tandem mass spectrometric detection. A noncompartmental method was used to determine the PK parameters of radotinib, including maximum plasma concentration (C_max), time to C_max (t_max), area under the Cp–time curve from time zero to the last quantifiable timepoint (AUC_last) and to infinity (AUC_inf), apparent clearance (CL/F), apparent volume of distribution (Vz/F) and terminal half-life (t_1/2). The effect of food was assessed by comparing the PK parameters under fasted and fed conditions, using the geometric mean ratios and corresponding 90% confidence intervals (CI) of C_max and AUC, considering the effect of period and sequence.

Results: Out of 24 healthy Asian participants enrolled in the study, the Cp–time data of radotinib obtained from 23 participants were pharmacokinetically evaluable. Under fasted conditions, the Cp of radotinib reached a median (interquartile range, IQR) C_max of 437 (338 – 609) ng/mL at a median (range) t_max of 3 (2 – 5) hours, followed by a rapid decline up to 12 hours and a gradual decrease thereafter. The median (IQR) values of AUC_last and AUC_inf were 7,553 (4,967 – 10,333) ng·h/mL and 7,850 (5,375 – 11,370) ng·h/mL, respectively, with median (IQR) percentage of AUC extrapolated (%AUC_ext) of 6.4 (3.2 – 10.28). The median (IQR) values of CL/F, Vz/F and t_1/2 were 51.0 (35.2 – 74.4) L/h, 1,315 (964 – 1,707) L and 17.5 (14.4 – 22.2) hours, respectively. Under fed conditions with standard meals, the Cp of radotinib reached a median (IQR) C_max of 1,266 (988 – 1,377) ng/mL at a median (range) t_max of 6 (5 – 18) hours. The median (IQR) values of AUC_last and AUC_inf were 27,233 (21,580 – 31,903) ng·h/mL and 28,759 (22,145 – 33,487) ng·h/mL, respectively, with median (IQR) %AUC_ext of 6.69 (3.38 – 11.05). The median (IQR) values of CL/F, Vz/F and t_1/2 were 13.9 (11.9 – 18.1) L/h, 336 (305 – 412) L and 17.1 (14.1 – 21.8) hours, respectively. The respective geometric mean values of C_max, AUC_last and AUC_inf under the fed conditions were 2.65-fold (90% CI, 2.27 – 3.10), 3.49-fold (90% CI, 2.98 – 4.08) and 3.49-fold (90% CI, 2.94 – 4.14) greater than those under the fasted conditions. The median value of t_max was longer by 3 hours under the fed conditions.

Conclusion: This is the first study that completely assessed the clinical PK characteristics and the food effect of radotinib in healthy volunteers. Following a single oral dose of radotinib under fasted conditions, the Cp of radotinib reached the C_max at a median of 3 hours post-dose and showed a median t_1/2 of 17.5 hours. Food intake delayed the absorption of radotinib and substantially increased the extent of absorption. The characteristics of radotinib determined in this study may provide a basis for optimizing radotinib therapy.

Acknowledgements: This study was approved by the Institutional Review Board of Severance Hospital (IRB number: 4-2024-0489). This work was supported by IL-YANG Pharmaceutical Co., the Research Institute of Pharmaceutical Sciences of Seoul National University, and the fourth phase of the Brain Korea 21 Program in 2025.