Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study.

Purposes Vactosertib is a new investigational inhibitor of activin receptor-like kinase 5. The objective of this study was to characterize vactosertib pharmacokinetics that are to be applied for subsequent clinical studies. Methods Vactosertib plasma concentration-time data were obtained from a multicenter, dose-escalation, first-in-human phase 1 study conducted in patients with advanced solid tumors. Each patient orally received a fixed dose of vactosertib with the range of 30 mg to 340 mg once daily under fasted condition. Pharmacokinetic analysis was performed using a non-compartmental method. Results Pharmacokinetic data were evaluable in 29 patients. Vactosertib was rapidly absorbed after the first dose with a median time to maximum concentration (tmax) of 1.2 h (interquartile range, 0.8-1.8 h) and quickly eliminated with a median terminal half-life (t1/2) of 3.2 h (2.2-4.2 h) over the dose range studied. Such trend was also observed after repeated doses for five days (median tmax, 1.5 h; median t1/2, 3.0 h). The area under the concentration-time curve within a dosing interval increased in proportion to dose. The median values of apparent clearance and volume of distribution were 29 L/h (21-44 L/h) and 133 L (77-222 L), respectively. The median accumulation ratio after repeated once-daily doses for five days was 0.87 (0.69-1.07). Conclusions Vactosertib pharmacokinetics were dose-proportional within tested dose range with negligible accumulation when administered once daily for five days. Considering the short half-life, it seems necessary to administer vactosertib twice- or thrice-daily to maintain its concentrations above minimum effective level over a dosing interval.

Population pharmacokinetics of vactosertib, a new TGF-ß receptor type Ι inhibitor, in patients with advanced solid tumors.

PURPOSE: Vactosertib, a novel inhibitor of transforming growth factor-ß 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 (Vc/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 Vc/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.