Pharmacokinetic/pharmacodynamic analysis of tacrolimus-induced QT prolongation in guinea pigs

Recently, several reports of clinical cases of QT prolongation and torsades de pointes, associated with the use of tacrolimus (FK506), have come to li ght. We have previously demonstrated FK506-induced QT prolongation in guine a pigs [Minematsu T,, et ai., Life Sci., 65, PL197-PL202 (1999)]. We now ex amined the relationship between QTc prolongation and the pharmacokinetics o f FK506 in guinea pigs, in order to evaluate the arrhythmogenicity of FIi50 6 when compared with that of quinidine sulfate (QND). Thus, dose-1 esponse relationships for FK506 (0.01 or 0.1 mg/h/kg) or QND (30 mg/h/kg) were inve stigated during and after intravenous infusion and also following intraveno us bolus administration of FK506 (0.2 mg/kg). The dose-response relationshi p between plasma drug concentration and QTc prolongation for FK506 and QND were subsequently analyzed using an effect compartment model. The pharmacod ynamic parameters thus obtained were as follows: k(E0) 2.72x10(-4) (min(-1) ), E-max 27.1 (ms), EC50 0.376 (ng/ml) for FK506; and k(E0) 0.148 (min(-1)) , K 8.41 (ms.ml/mu g) for QND. The anti-clockwise hysteresis observed for F K506-induced QT prolongation was successfully analyzed by the present pharm acokinetic/pharmacodynamic model, which may provide a rational basis for de veloping a clinical dosing regimen to avoid possible QT prolongation induce d by FK506.