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- Title
Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors.
- Authors
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.
- Abstract
<bold>Purpose: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
SOUTH Korea; PHARMACOKINETICS; BODY mass index; MONTE Carlo method; DEMOGRAPHIC characteristics; TUMORS; THERAPEUTIC use of antineoplastic agents; PUBLIC health surveillance; CLINICAL trials; ANTINEOPLASTIC agents; CHEMICAL laboratory equipment; LONGITUDINAL method
- Publication
Cancer Chemotherapy & Pharmacology, 2020, Vol 85, Issue 1, p173
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-019-03979-z