Details

Autor(en) / Beteiligte

• Jung, Su Young
• Yug, Ji Seob
• Clarke, Jeffery M.
• Bauer, Todd M.
• Keedy, Vicki L.
• Hwang, Sunjin
• Kim, Seong-Jin
• Chung, Eun Kyoung
• Lee, Jangik I.

Titel

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

Ist Teil von

• Cancer chemotherapy and pharmacology, 2020, Vol.85 (1), p.173-183

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.