Limited Sampling Strategy for the Estimation of Tacrolimus Area Under the Concentration-Time Curve in Chinese Adult Liver Transplant Patients

<b><i>Objectives:</i></b> Limited sampling strategies (LSS) have been proposed as an alternative method for estimating area under concentration-time curve (AUC) of immunosuppressive agent tacrolimus (TAC). In this study, we aimed to develop the LSS models for predicting AUC of TAC in Chinese liver transplant patients. <b><i>Methods:</i></b> Twenty-eight adult liver transplant patients receiving immunosuppressive regimen including TAC were enrolled. A total of 47 pharmacokinetic profiles were obtained after 1 or 3 weeks therapy. TAC concentrations were determined before dose (0 h) and at 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after dosing by LC-MS/MS assay. Optimal subset regression analysis was used to establish the models for estimating TAC AUC_0-12. Prediction error (PE) and absolute PE were calculated. The agreement between predicted and measured AUC_0-12 was investigated by Bland-Altman analysis. The obtained models were validated by bootstrap analysis. The prediction performance among various <i>CYP3A5</i> and <i>ABCB1</i> genotypes was compared. The models selected from previous published studies were also validated using our data. <b><i>Results:</i></b> Twenty-eight models including 1, 2, 3 and 4 blood time points sampling were established (r² = 0.653-0.979). The best model for prediction of TAC AUC_0-12 was 0.81 + 1.73C₁ + 1.32C₂ + 3.87C₄ + 3.75C₈ (r² = 0.979). Forty profiles (85.1%) had estimated TAC AUC_0-12 within ±15% of observed TAC AUC_0-12. Model with C₀-C₂ (r² = 0.880) can be used for outpatients who need monitoring to be carried out in a short period. We also found that <i>ABCB1</i> genotype may be a reason of variation in the prediction performance. There was good correlation between predicted and measured AUC_0-12 (r² = 0.880-0.928) by using models from previous studies with sample collected within 4 h post dose. <b><i>Conclusion:</i></b> The LSS is an effective approach for estimation of full TAC AUC_0-12 in Chinese liver transplant patients.