Evaluation of limited-sampling strategies to calculate AUC (0-24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus
Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C ) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, b...
Saved in:
Published in | Frontiers in pharmacology Vol. 14; p. 1044050 |
---|---|
Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
14.03.2023
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C
) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC
and
genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC
formulas and dose requirements.
We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC
and
genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC
normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC
model. We compared the performance of this model with two pediatric LSS-AUC
equations for clinical validation.
Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9 years). When normalizing AUC
by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1 ng*h/mL/mg/kg,
< 0.05). C
had a poor fit with AUC
(
= 0.5011). The model which included C
, C
and C
, showed the best performance to predict LSS-AUC
(
= 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC
, in comparison to other LSS equations.
Estimation of LSS-AUC
with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different
genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Pharmacogenetics and Pharmacogenomics, a section of the journal Frontiers in Pharmacology Reviewed by: Ashwin Karanam, Pfizer (United States), United States Nelson Varela, University of Chile, Chile Edited by: Maria Ana Redal, University of Buenos Aires, Argentina These authors have contributed equally to this work Lars Pape, Essen University Hospital, Germany |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2023.1044050 |