Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36–64 years) and the mean weight 70.49 kg (50–111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC 0–12) was calculated by the trapezoidal rule. Using 0–4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC 0–4) was calculated assuming C 0 and C 12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5 ± 13.8 ng/mL) was reached at 2.3 ± 1.5 h. When target trough levels were achieved (10–20 ng/mL), the mean tacrolimus exposure was 230.6 ± 59.2 ng h/mL (120.14–327.7) ( n = 19). Correlation between AUC 0–12 and C 0 was relatively good ( r 2 = 0.74). Between individual time points, C 4 showed the best correlation ( r 2 = 0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC 0–4 ( r 2 = 0.98), as a good approach to patients with a poor response to treatment.