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Background: Dasatinib is administered at a fixed starting dosage of 100 mg once daily regardless of patient-specific factors. However, such fixed dosing may not be optimal for the treatment of Asian patients with chronic myeloid leukemia in chronic phase (CP-CML)., Patients and Methods: The dose-limiting toxicities (DLTs) and molecular responses (MRs) of dasatinib therapy were evaluated using clinical data obtained from 102 patients newly diagnosed with CP-CML at 17 hospitals in South Korea., Results: By 36 months after the initiation of a fixed dose regimen of dasatinib 100 mg once daily as the first-line therapy, 55.9% of patients experienced at least one type of DLT. The 3 most frequent DLTs were thrombocytopenia (45.5%), pericardial or pleural effusion (30.9%), and anemia (7.3%). Patients with higher dasatinib dose adjusted for body weight (Dose/BW) had a greater rate of DLT occurrence (logit [P] = 1.58 × [Dose/BW] - 2.27, P = .03). As median Dose/BW increased from 1.23 to 2.00 mg/kg, the rate of DLT occurrence increased from 43.5% to 66.7% (P = .03). However, Dose/BW did not affect the achievement rate of major MR (60.9% to 69.6%, P = .92)., Conclusion: The starting dosage of dasatinib may need to be reduced (eg, 80 mg once daily or lower) for Asian patients with CP-CML, especially with lighter BW, to alleviate the risk of DLT occurrence without compromising the achievement of MR., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Vactosertib, a novel inhibitor of transforming growth factor-β type Ι receptor, is under development for the treatment of various cancers. The objective of this study was to characterize the population pharmacokinetics of vactosertib in patients with solid tumors., Methods: Vactosertib population pharmacokinetics was assessed by nonlinear mixed-effects modelling of plasma concentration-time data obtained from a first-in-human phase 1 trial conducted in patients with advanced solid tumors. The final population pharmacokinetic model was constructed by assessing the effect of covariates on pharmacokinetic parameters including demographic characteristics, laboratory values, hepatic and renal function, and concomitant medications. The robustness of the final model was evaluated using a bootstrap method as well as visual predictive check based on Monte Carlo simulations and goodness-of-fit plots., Results: A total of 559 concentrations from 29 patients were available for pharmacokinetic analysis. A two-compartment linear model with first-order absorption and absorption lag time adequately described the population pharmacokinetics of vactosertib. The estimates of apparent clearance (CL/F) and volume of central compartment (V c /F) were 31.9 L/h (inter-individual variability, 0.481) and 82.9 L (inter-individual variability, 0.534), respectively. The mixture model accounts for both typical absorption profile in the majority of patients and distinct profile in some patients with uncommon gastrointestinal conditions. Body mass index was significantly associated with V c /F., Conclusions: The model developed in this study adequately describes the population pharmacokinetics of vactosertib in patients with advanced solid tumors. The pharmacokinetic characteristics assessed using the model would provide useful quantitative information to assist the future clinical development of vactosertib.

Purpose: Lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Individuals concomitantly taking lobeglitazone and a CYP3A4 inhibitor may experience some adverse effects secondary to increased systemic exposure to lobeglitazone. To address such potential concern, we evaluated the effects of ketoconazole, a prototypic CYP3A4 inhibitor, on the pharmacokinetic (PK) properties and associated adverse effects of lobeglitazone., Methods: A PK drug-drug interaction study was conducted in healthy individuals between 20 and 45 years old in a randomized, open-label, 2-way crossover design. Even though the PK study was performed on a single dose of lobeglitazone, multiple ketoconazole doses were given to ensure that the full extent of inhibition of CYP3A4 was maintained during the PK sampling. All study participants received a single oral dose of lobeglitazone 0.5 mg with or without 9 oral 200-mg doses of ketoconazole pretreatment twice daily. The primary PK parameter end points (AUC and Cmax) were estimated using noncompartmental analysis, and the 90% CIs for the geometric mean ratios (ratio of lobeglitazone and ketoconazole to lobeglitazone alone) were investigated. Tolerability (adverse events, vital signs, ECG, and laboratory tests) was also assessed., Findings: A total of 24 Korean men (mean age, 26 years; age range, 20-32 years; mean weight, 68 kg; weight range, 59-81 kg) completed the study and were evaluable for lobeglitazone PK properties and tolerability. The mean (SD) Cmax values of lobeglitazone with and without ketoconazole were 49 (7) ng/mL and 48 (6) ng/mL at 1.5 and 1.0 hours after dosing, respectively. The mean (SD) AUC∞ values were 532 (117) ng·h/mL and 405 (110) ng·h/mL, respectively. Although the Cmax was not significantly affected, the geometric mean ratio for AUC∞ was increased by a point estimate of 1.33 (90% CI, 1.23-1.44). A single oral administration of lobeglitazone 0.5 mg with or without ketoconazole pretreatment did not produce any clinically significant adverse effects on vital signs, 12-lead ECG profiles, or laboratory tests., Implications: The administration of lobeglitazone, 0.5 mg alone or in combination with multiple doses of ketoconazole, was generally well tolerated. The systemic exposure of lobeglitazone was increased to a modest extent by pretreatment with 9 twice-daily doses of ketoconazole. Clinicaltrials.gov identifier: NCT01330563., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)