Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients

Abstract

Because tacrolimus (Tac) has a narrow therapeutic index and highly inter- and intra-individual variable pharmacokinetic (PK) characteristics, monitoring of drug exposure is recommended, but limited data are available on the kinetics of Tac in paediatric renal transplant recipients, especially of limited sampling strategies. To investigate the correlation between Tac trough level (TL) and the 0-12 h area under the curve (AUC), and the value of abbreviated AUC monitoring, we evaluated 12 h PK profiles in 27 children at least 1 year after transplantation. There was a significant discrepancy between Tac TLs and 0-12 h AUC (r = 0.60). Every time point, different from C(0), gave a better prediction for the drug exposure, with C(4) and C(6) as best predictors (r = 0.93 and r = 0.92, respectively). The 0-12 h AUC was estimated with great precision by the use of a two- or three-point sampling strategy, and the latter is more time-point independent. In paediatric renal transplant recipients on Tac maintenance therapy, whose condition is stable, Tac TL is not a reliable tool for the estimation of drug exposure. Abbreviated monitoring, especially at three points in time, give reliable predictions of the complete 0-12 h AUC. We suggest a 0-12 h AUC of around 150 ng x h/ml for stable paediatric renal transplant recipients 1 year after transplantation and around 100 ng x h/ml in the following years. Target AUC values should be further established for paediatric transplant recipients according to the time after transplantation.

Limited Sampling Strategy for Estimating Individual Exposure of Tacrolimus in Pediatric Kidney Transplant Patients

“…Our results demonstrated that the correlation coefficients (r 2 ) between C 0h and AUC were moderate, in both the original dataset and the dataset used for external validation. This is in agreement with the previous reports on kidney-transplanted children showing that correlation coefficients (r 2 ) may vary widely, between 0.30 and 0.79, 10,11,[18][19][20][21][22] suggesting that C 0h only is not a good surrogate marker of tacrolimus AUC, despite its widespread use for monitoring tacrolimus treatment, 1 AUCbased dosage individuation remains the gold standard 8 for dosage adaptation as it was effective in optimizing efficacy and reducing both rejection or toxicity. 8 The LSS approach facilitates dosage adaptation in clinical practice by providing an ethical, cost-and timeeffective method to monitor tacrolimus.…”

“…Indeed, LSS approach for tacrolimus has been widely developed in adult organ transplant patients 9,23 but not in children. Only 2 LSS using multiple regression analysis have been published, 10,11 and their application remains difficult in clinical practice, as up to 4 samples are collected up to 6 hours postdose, and there is no external validation. In our current investigation, we focused on the development and validation of clinically reliable LSS for estimating AUC in pediatric patients, with samples limited to 3, collected within 3 hours of drug administration.…”

“…Therefore, limited sampling strategies (LSS) have been proposed to overcome this problem, and numerous LSS approaches have been developed and validated for adult organ transplant patients, 9 yet, very little data are available for children. [10][11][12] In addition, none of them made a prospective validation in an independent pediatric dataset to avoid biased results related to the original dataset used for developing the population pharmacokinetic model and LSS. 13 From clinical practice perspective, another important issue regarding the development of LSS is the selection of time points.…”

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

“…However, some studies found that C 0 could not reflect the inter-individual difference of total TAC exposure reliably. Poor correlation between the TAC C 0 and AUC 0-12 was found in kidney [8,9] and liver [10,11] transplant patients.…”

“…Results: Twenty-eight models including 1, 2, 3 and 4 blood time points sampling were established (r 2 = 0.653-0.979). The best model for prediction of TAC AUC 0-12 was 0.81 + 1.73C 1 + 1.32C 2 + 3.87C 4 + 3.75C 8 (r 2 = 0.979). Forty profiles (85.1%) had estimated TAC AUC 0-12 within ±15% of observed TAC AUC 0-12 .…”