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

被引:45
作者
Jung, Su Young [1 ,2 ]
Hwang, Sunjin [3 ]
Clarke, Jeffery M. [4 ]
Bauer, Todd M. [5 ]
Keedy, Vicki L. [6 ]
Lee, Hukeun [7 ]
Park, Neunggyu [7 ]
Kim, Seong-Jin [3 ]
Lee, Jangik, I [1 ,2 ]
机构
[1] Seoul Natl Univ, Coll Pharm, Dept Pharm, 1 Gwanak Ro, Seoul 08826, South Korea
[2] Seoul Natl Univ, Res Inst Pharmaceut Sci, Seoul, South Korea
[3] MedPacto Inc, Seoul, South Korea
[4] Duke Univ, Med Ctr, Durham, NC USA
[5] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA
[6] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA
[7] Natl Canc Ctr, Natl OncoVenture, Goyang, South Korea
关键词
Vactosertib; ALK5; inhibitor; Pharmacokinetics; First-in-human study; Solid tumors; TGF-BETA; TRIAL;
D O I
10.1007/s10637-019-00835-y
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (t(max)) of 1.2 h (interquartile range, 0.8-1.8 h) and quickly eliminated with a median terminal half-life (t(1/2)) 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 t(max), 1.5 h; median t(1/2), 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.
引用
收藏
页码:812 / 820
页数:9
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