Date: Tuesday, May 5, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Purpose: Calcineurin-inhibitors (CNI) have a narrow therapeutic index and dosing is difficult due to inter- and intra-individual variation in pharmacokinetics (PK). Polymorphisms in genes involved in drug metabolism can play a critical role in individual exposure. Data concerning long-term CNI exposure in relation to dose in children are scarce and in general based upon trough levels. We present the longitudinal follow up of 12-hour CNI PK in relation to dose, clinical and genetic factors in a cohort pediatric renal allograft recipients.
Methods: Retrospective single center study in subjects after renal transplantation (age 0-20 yrs) with annual PK assessments (6-point AUC0-12hr) for tacrolimus (Tac) or cyclosporine A (CsA). Co-medication, clinical and laboratory data were retrieved from the files. Analysis of polymorphisms in CYP3A4, CYP3A5, CYP3A7, POR and ABCB1 was performed.
Results: We collected 180 "full" AUC 0-12hr for Tac, 56 for CsA in 51 children. Mean age at Tx: 9.9 yrs(1-19); FU after Tx: 4.6 yrs (0-16). Dose-corr. exposure (AUC0-12 / dose in mg/kg) increased with age: 854 (mean) in <5 yrs to 2702 >15yrs); 817 to 1787 ng*hr/ml per mg/kg in Tac and CsA resp. (p< 0.01). Correction for dose per m2 body surface (BS) demonstrated stable dose-corr. exposure for ages <15 yrs, and was higher only for >15 yrs (Tac: <5yrs-15 yrs: 44 (95%CI: 40-48) >15yrs: 73.4 ng hr/ml per mg/m2; CsA: 40 (CI 36-44) vs. 52. CYP3A5 genotype was an important co-determinant of dose-corr. exposure for Tac (2.1 higher dose-req. in *1 vs *3/3), but not for CsA. *1 carriers had an attenuated increase in dose-corr.exposure into adulthood (27 vs. 39 in >15yrs; *3/3: 48 vs. 82 resp.)
Conclusion: Dose-corr exposure according to BS, in contrast to bodyweight, demonstrates stable CNI dose requirements in children <15 yrs. Polymorphisms in CYP3A5 are important for individual dose requirements in patients on Tac and modify the effect of age. In contrast, CsA is not affected by CYP3A5. Our data suggest that CNI dosing per m2 in children after renal transplantation would be less prone to variation in exposure with age and thus preferred. CYP3A5 genotype only aids in predicting Tac dose requirements.
To cite this abstract in AMA style:Knops N, Dyck Mvan, Levtchenko E, Kuypers D, Herman J. New Insights in Clinical and Genetic Determinants of Longitudinal Dose-Corrected CNI Exposure in Children After Renal Transplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/new-insights-in-clinical-and-genetic-determinants-of-longitudinal-dose-corrected-cni-exposure-in-children-after-renal-transplantation/. Accessed May 7, 2021.
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