2. A population pharmacokinetic model not predict the optimal starting dose of tacrolimus in pediatric renal transplant recipients in a prospective study; lessons learned and model improvement

L.M. Andrews, B.C.M. de Winter, E.A.M. Cornelissen, H. de Jong, D.A. Hesselink, M.F. Schreuder, R.J.M. Bruggemann, T. van Gelder, K. Cransberg

Wednesday 4 march 2020

0:00 - 0:00h at Toon Hermans Foyer

Parallel session: Postersessie 1 – Klinische abstracts

Background: Multiple clinical, demographic and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus predose concentration (C0). This study was done to investigate whether adaptation of the tacrolimus starting dose according to a validated dosing algorithm increases the proportion of pediatric kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady state.

Methods: This was a multi-center, single arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, CYP3A5 genotype and donor status (living vs. deceased donor). After five doses the tacrolimus predose concentration was determined and the dose adjusted accordingly.

Results: At the interim analysis, 31% of children had a tacrolimus predose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. CYP3A5 genotype, hematocrit and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which CYP3A5 genotype was incorporated. Both models were successfully internally and externally validated.

Conclusions: The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are CYP3A5 expresser.