TY - JOUR
T1 - A semimechanistic population pharmacokinetic and pharmacodynamic model incorporating autoinduction for the dose justification of TAS-114
AU - Araki, Hikari
AU - Takenaka, Toru
AU - Takahashi, Koichi
AU - Yamashita, Fumiaki
AU - Matsuoka, Kazuaki
AU - Yoshisue, Kunihiro
AU - Ieiri, Ichiro
N1 - Funding Information:
All research activities were funded by Taiho Oncology, Inc., and Taiho Pharmaceutical Co., Ltd. We thank all of the participating subjects in the clinical studies, the study investigators, study nurses, study monitors, data managers, and all team members of TAS-114. We also thank Editage for English-language editing services.
Funding Information:
All research activities were funded by Taiho Oncology, Inc., and Taiho Pharmaceutical Co., Ltd.
Publisher Copyright:
© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2022/5
Y1 - 2022/5
N2 - TAS-114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. Its maximum tolerated dose (MTD) was determined from a safety perspective in a combination study with capecitabine; however, its inhibitory effects on DPD activity were not assessed in the study. The dose justification to select its MTD as the recommended dose in terms of DPD inhibition has been required, but the autoinduction profile of TAS-114 made it difficult. To this end, an approach using a population pharmacokinetic (PPK)/pharmacodynamic (PD) model incorporating autoinduction was planned; however, the utility of this approach in the dose justification has not been reported. Thus, the aim of this study was to demonstrate the utility of a PPK/PD model incorporating autoinduction in the dose justification via a case study of TAS-114. Plasma concentrations of TAS-114 from 185 subjects and those of the endogenous DPD substrate uracil from 24 subjects were used. A two-compartment model with first-order absorption with lag time and an enzyme turnover model were selected for the pharmacokinetic (PK) model. Moreover, an indirect response model was selected for the PD model to capture the changes in plasma uracil concentrations. Model-based simulations provided the dose justification that DPD inhibition by TAS-114 reached a plateau level at the MTD, whereas exposures of TAS-114 increased dose dependently. Thus, the utility of a PPK/PD model incorporating autoinduction in the dose justification was demonstrated via this case study of TAS-114.
AB - TAS-114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. Its maximum tolerated dose (MTD) was determined from a safety perspective in a combination study with capecitabine; however, its inhibitory effects on DPD activity were not assessed in the study. The dose justification to select its MTD as the recommended dose in terms of DPD inhibition has been required, but the autoinduction profile of TAS-114 made it difficult. To this end, an approach using a population pharmacokinetic (PPK)/pharmacodynamic (PD) model incorporating autoinduction was planned; however, the utility of this approach in the dose justification has not been reported. Thus, the aim of this study was to demonstrate the utility of a PPK/PD model incorporating autoinduction in the dose justification via a case study of TAS-114. Plasma concentrations of TAS-114 from 185 subjects and those of the endogenous DPD substrate uracil from 24 subjects were used. A two-compartment model with first-order absorption with lag time and an enzyme turnover model were selected for the pharmacokinetic (PK) model. Moreover, an indirect response model was selected for the PD model to capture the changes in plasma uracil concentrations. Model-based simulations provided the dose justification that DPD inhibition by TAS-114 reached a plateau level at the MTD, whereas exposures of TAS-114 increased dose dependently. Thus, the utility of a PPK/PD model incorporating autoinduction in the dose justification was demonstrated via this case study of TAS-114.
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U2 - 10.1002/psp4.12747
DO - 10.1002/psp4.12747
M3 - Article
C2 - 34951129
AN - SCOPUS:85121640614
VL - 11
SP - 604
EP - 615
JO - CPT: Pharmacometrics and Systems Pharmacology
JF - CPT: Pharmacometrics and Systems Pharmacology
SN - 2163-8306
IS - 5
ER -