Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs: pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect.
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 QTprolongation. Such a hysteresis pattern for QTprolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.
Minematsu
T
T
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Ohtani
H
H
Yamada
Y
Y
Sawada
Y
Y
Sato
H
H
Iga
T
T
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D006168:Guinea Pigs; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D016559:Tacrolimus / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D016559:Tacrolimus