Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients

Kotaro Itohara, Ikuko Yano, Shunsaku Nakagawa, Atsushi Yonezawa, Tomohiro Omura, Satoshi Imai, Takayuki Nakagawa, Atsuro Sawada, Takashi Kobayashi, Akira Tochio, Kaoru Sakai, Kojiro Taura, Osamu Ogawa, Kazuo Matsubara

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is useful for evaluating differences in drug exposure among special populations, but it has not yet been employed to evaluate the absorption process of tacrolimus. In this study, we developed a minimal PBPK model with a compartmental absorption and transit model for renal transplant patients using available data in the literature and clinical data from our hospital. The effective permeability value of tacrolimus absorption and parameters for the single adjusting compartment were optimized via sensitivity analyses, generating a PBPK model of tacrolimus for renal transplant patients with good predictability. Next, we extrapolated the pharmacokinetics of tacrolimus for liver transplant patients by changing the population demographic parameters of the model. When the physiological parameters of a population with normal liver function were changed to those of a population with impaired hepatic function (Child-Pugh class A) in the constructed renal transplant PBPK model, the predicted tacrolimus concentrations were consistent with the observed concentrations in liver transplant patients. In conclusion, the constructed tacrolimus PBPK model for renal transplant patients could predict the pharmacokinetics in liver transplant patients by slightly reducing the hepatic function, even at three weeks post-transplantation.

Original languageEnglish
Article number100423
JournalDrug Metabolism And Pharmacokinetics
Volume42
DOIs
Publication statusPublished - 2022 Feb
Externally publishedYes

Keywords

  • Liver transplantation
  • PBPK
  • Renal transplantation
  • Simcyp
  • Tacrolimus

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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