Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs

Pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect

T. Minematsu, Hisakazu Ohtani, Y. Yamada, Y. Sawada, H. Sato, T. Iga

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QT prolongation. Such a hysteresis pattern for QT prolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.

Original languageEnglish
Pages (from-to)533-554
Number of pages22
JournalJournal of Pharmacokinetics and Pharmacodynamics
Volume28
Issue number6
DOIs
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Pharmacodynamics
Pharmacokinetics
Tacrolimus
Guinea Pigs
Hysteresis
Blood

Keywords

  • Guinea pigs
  • Pharmacokinetic/pharmacodynamic modeling
  • QT prolongation
  • Quinidine
  • Tacrolimus

ASJC Scopus subject areas

  • Pharmacology
  • Catalysis

Cite this

@article{ff190527db85422f946a02b3bfae9a87,
title = "Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs: Pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect",
abstract = "Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QT prolongation. Such a hysteresis pattern for QT prolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.",
keywords = "Guinea pigs, Pharmacokinetic/pharmacodynamic modeling, QT prolongation, Quinidine, Tacrolimus",
author = "T. Minematsu and Hisakazu Ohtani and Y. Yamada and Y. Sawada and H. Sato and T. Iga",
year = "2001",
doi = "10.1023/A:1014460404352",
language = "English",
volume = "28",
pages = "533--554",
journal = "Journal of Pharmacokinetics and Pharmacodynamics",
issn = "1567-567X",
publisher = "Springer New York",
number = "6",

}

TY - JOUR

T1 - Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs

T2 - Pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect

AU - Minematsu, T.

AU - Ohtani, Hisakazu

AU - Yamada, Y.

AU - Sawada, Y.

AU - Sato, H.

AU - Iga, T.

PY - 2001

Y1 - 2001

N2 - Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QT prolongation. Such a hysteresis pattern for QT prolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.

AB - Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QT prolongation. Such a hysteresis pattern for QT prolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.

KW - Guinea pigs

KW - Pharmacokinetic/pharmacodynamic modeling

KW - QT prolongation

KW - Quinidine

KW - Tacrolimus

UR - http://www.scopus.com/inward/record.url?scp=0035732087&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035732087&partnerID=8YFLogxK

U2 - 10.1023/A:1014460404352

DO - 10.1023/A:1014460404352

M3 - Article

VL - 28

SP - 533

EP - 554

JO - Journal of Pharmacokinetics and Pharmacodynamics

JF - Journal of Pharmacokinetics and Pharmacodynamics

SN - 1567-567X

IS - 6

ER -