Generic tacrolimus in renal transplantation: trough blood concentration as a surrogate for drug exposure.

The use of generic formulations of immunosuppressive drugs in place of brand-name drugs offers considerable cost savings. Adoport (Sandoz, Camberly, Surrey, United Kingdom), an immediaterelease, twice-daily, oral tacrolimus preparation (1), was introduced to the United Kingdom in August 2010. Although both pharmaceutical and bioequivalence with the originator product, Prograf (Astellas Pharma US, Inc., Deerfield, IL), have been demonstrated for licensing purposes (2), recent guidance on the substitution of generic immunosuppressant drugs has highlighted the possibility that the relationship between the exposure to the drug and the surrogate marker may vary between formulations (3), particularly in routine clinical practice. The narrow therapeutic index of tacrolimus (4) and the potential adverse consequences of subtherapeutic and toxic concentrations necessitate close monitoring of patients’ exposure to the drug. Twelve-hour pharmacokinetic profiles are the most exact method for monitoring the area under the concentration-time curve (AUC) and hence the total tacrolimus exposure. However, they require that the tacrolimus concentration is measured at a minimum of six different time points (5). Instead, tacrolimus trough concentrations (C0) are commonly measured as a surrogate for the AUC, although there have been conflicting reports regarding the correlation of C0 with AUC and systemic exposure (6Y10). For cost reasons, the South West Transplant Centre switched from administering Prograf to Adoport for de novo transplant recipients on November 1, 2010. We sought to evaluate the relationship between C0 and the AUC in patients receiving Adoport during the acute phase after renal transplantation. Serial tacrolimus concentrations were measured on day 4 or 5 after transplantation in 16 sequential patients (11 men and 5 women) not receiving medications known to interact with tacrolimus. The mean age was 56 years (range, 31Y72 years). Thirteen patients received donation after cardiac death organs, and three patients received living-donor transplants. Thirteen patients received basiliximab at induction, for whom Adoport was commenced on day 0 at 0.10 mg/kg in two divided doses with a target C0 of 8 to 10 ng/mL. Three patients received alemtuzumab at induction, for whom Adoport was commenced on day 3 after transplantation at a dose of 2 mg twice daily with a target C0 of 5 to 7 ng/mL. It was intended that patients fasted overnight before administration of Adoport to control for the effects of food on tacrolimus absorption (11). Whole-blood samples were collected before administration and at 0.5, 1, 2, 4, 8, and 12 hr after administration of Adoport. Tacrolimus concentrations were determined in ethylenediaminetetraacetic acid whole blood using liquid chromatographyYmass spectrometry. The lower limit of quantification was 2.0 ng/mL. The AUC was calculated from the timeversus-tacrolimus plot, using the linear trapezoid rule. The C0 values were determined by using the whole-blood tacrolimus concentration measured at 12 hr. The mean dose of Adoport was 0.09 (T0.03) mg/kg per day, and the mean AUC was 136.0 (T78.2) ng hr/mL. The mean C0 was 7.9 (T4.8) ng/mL. The linear regression coefficient of multiple determination (r) for the relationship between C0 and the AUC was 0.92. The mean dose-normalized AUC was 3327 (T2389) ng hr/mL. The mean dosenormalized C0 was 196 (T146) ng/mL. The 12-hr pharmacokinetic profiles for these patients, and the correlation between the AUC and the C0, are shown in Figure 1. The coefficient of determination for the relationship between C0 and AUC for Prograf has been reported to lie between 0.125 and 0.86 (7, 8, 10, 12Y14). The variability in these correlations may be attributable to a number of factors, including differences in the