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

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Abstract

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 (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.

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Acknowledgements

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).

Funding

This study was sponsored by MedPacto, Inc.

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Author notes

    Authors and Affiliations

    1. Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea

      Su Young Jung & Jangik I. Lee

    2. Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

      Su Young Jung & Jangik I. Lee

    3. Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

      Ji Seob Yug & Eun Kyoung Chung

    4. Duke University Medical Center, Durham, NC, USA

      Jeffery M. Clarke

    5. Sarah Cannon Research Institute/Tennessee Oncology PLLC, Nashville, TN, USA

      Todd M. Bauer

    6. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

      Vicki L. Keedy

    7. MedPacto, Inc, Seoul, Republic of Korea

      Sunjin Hwang & Seong-Jin Kim

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    1. Su Young Jung
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    Correspondence to Eun Kyoung Chung or Jangik I. Lee.

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    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.

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

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    Eun Kyoung Chung and Jangik I. Lee contributed equally to this work.

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    Jung, S.Y., Yug, J.S., Clarke, J.M. et al. Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol 85, 173–183 (2020). https://doi.org/10.1007/s00280-019-03979-z

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