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

  • Su Young Jung
  • Ji Seob Yug
  • Jeffery M. Clarke
  • Todd M. Bauer
  • Vicki L. Keedy
  • Sunjin Hwang
  • Seong-Jin Kim
  • Eun Kyoung ChungEmail author
  • Jangik I. LeeEmail author
Original Article



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.


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.


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.


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.


Vactosertib TGF-β signaling inhibitor Population pharmacokinetics Phase 1 Solid tumors 



The authors would like to acknowledge all the patients and study personnel who participated in the phase 1 study. This work was supported by the Research Institutes of Pharmaceutical Science in Seoul National University. Additional support was provided by the National OncoVenture/National Cancer Center funded by Ministry of Health and Welfare, Republic of Korea (No. HI17C2196).


This study was sponsored by MedPacto, Inc.

Compliance with ethical standards

Conflict of interest

JIL and EKC have received research funding from MedPacto, Inc. JMC, TMB and VLK received grant from MedPacto, Inc. for conduct of the phase 1 clinical trial as principal investigators. JMC has received research grant as a principal investigator from Bristol-Myers Squibb, Eli Lilly, Genentech, Spectrum, Adaptimmune, MedPacto, Bayer, AbbVie, and Moderna, and served as an advisory consultant for AstraZeneca, Guardant, Merck and Eli Lilly. TMB has received research grant from Daiichi Sankyo, Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca, Merck, Eli Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Roche, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Onyx, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, and ARMO Biosciences. VLK is a consultant for Karyopharm Therapeutics, and has research funding from Plexxicon, Eli Lilly, Daiichi Sankyo, BioMed Valley Discoveries, Immune Design, GlaxoSmithKline, TRACON Pharma, and Advenchen Laboratories. SJK has a personal financial interest as a shareholder in MedPacto, Inc. SH is an employee of MedPacto, Inc. Other remaining authors have nothing to disclose.

Ethical approval

All procedures involving human participants performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, College of PharmacySeoul National UniversitySeoulRepublic of Korea
  2. 2.Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulRepublic of Korea
  3. 3.Department of Pharmacy, College of PharmacyKyung Hee UniversitySeoulRepublic of Korea
  4. 4.Duke University Medical CenterDurhamUSA
  5. 5.Sarah Cannon Research Institute/Tennessee Oncology PLLCNashvilleUSA
  6. 6.Vanderbilt-Ingram Cancer CenterVanderbilt University Medical CenterNashvilleUSA
  7. 7.MedPacto, IncSeoulRepublic of Korea

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