Abstract
STUDY OBJECTIVE: The objective was to compare tacrolimus AUC(0-12) determined by Non-Compartmental Analysis (NCA) using intensive sampling to Maximum a Posteriori-Bayesian (MAP-Bayesian) estimates from robust (n = 9 samples/subject) and sparse (n = 2 samples/subject) sampling in 67 stable KTRs and a validation group of similar patients. DESIGN: This open-label, prospective, single center 12-h PK study included nine serial samples collected in KTRs to determine steady-state NCA tacrolimus AUC(0-12) . SETTING: This study was conducted at a single site within a large, urban hospital in the western New York area. PATIENTS: This study described tacrolimus pharmacokinetics in stable kidney transplant recipients on maintenance tacrolimus therapy. INTERVENTION: Robust and sparse AUC(0-12) estimates by a MAP-Bayesian approach were obtained using the Advanced Dosing Solutions (AdDS) and ADAPT5 freeware. Limited sampling strategies were evaluated using the original population PK model (n = 67), which was also assessed using a validation group (n = 15). AUC(0-12) agreement was tested by paired t-tests with intraclass correlation coefficient (ICC) and Bland Altman analysis. MEASUREMENTS AND MAIN RESULTS: A total of 35 Black and 32 White stable KTRs (estimated glomerular filtration rate [eGFR] = 55.2 ± 15.7 mL/min/1.73m(2) ) received the tacrolimus dose of 3.4 ± 1.7 mg/study with troughs of 6.8 ± 1.8 ng/mL. The NCA-AUC(0-12) was 123.8 ± 33.6 μg·h/L compared to MAP-Bayesian estimates for Robust-AUC(0-12) of 124.7 ± 33.3 μg·h/L and optimal 2-specimen Sparse-AUC(0-12) of 119.7 ± 32.7 μg·h/L for the training group. Comparison of Robust-AUC(0-12) to NCA-AUC(0-12) had an ICC of 0.96 (p = 0.99) while comparison of Robust-AUC(0-12) to Sparse-AUC(0-12) using Pre-dose trough [C(t(0h) )] and 1 h [C(t(1h) )] resulted in an ICC of 0.93 (p = 0.014). In the validation group, 5 Black and 10 White KTRs (eGFR = 56.4 ± 16.8 mL/min/1.73m(2) ) received a mean tacrolimus dose of 1.9 ± 1.2 mg/study with a trough of 6.0 ± 1.7 ng/mL. The validation group's NCA-AUC(0-12) (88.4 ± 33.1 μg·h/L) was comparable to Robust-AUC(0-12) (85.1 ± 33.8 μg·h/L, ICC = 0.93; p = 0.12) and Sparse-AUC(0-12) determined from C(t(0h) ) and C(t(4h) ) (86.7 ± 33.9 μg·h/L, ICC = 0.91; p = 0.61). CONCLUSION: MAP-Bayesian estimation for patient-specific AUC(0-12) using sparse, two-specimen sampling is comparable to NCA and may enhance tacrolimus TDM in stable KTRs.