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.

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We would like to acknowledge the valuable contributions of the patients who participated in the phase 1 study, their families, and study personnel. This study 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).


The phase 1 study and pharmacokinetic analysis were sponsored by MedPacto, Inc.

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Corresponding author

Correspondence to Jangik I. Lee.

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Conflict of interest

JIL has received research funding from MedPacto, Inc. as an advisory consultant. JMC, TMB, and VLK received grant from MedPacto, Inc. to perform 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 and SH are a CEO and an employee of MedPacto, Inc., respectively. Other remaining authors have nothing to disclose.

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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. This article does not contain any studies with animals performed by any of the authors.

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Informed consents were obtained from all individual participants enrolled in the phase 1 study.

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Jung, S.Y., Hwang, S., Clarke, J.M. et al. 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. Invest New Drugs 38, 812–820 (2020).

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  • Vactosertib
  • ALK5 inhibitor
  • Pharmacokinetics
  • First-in-human study
  • Solid tumors