Model Informed preciSion doSIng tO iNdividualise and optimize pharmacotherapeutic treatment (MISSION) - Appendix 1: Prospective evaluation of Model informed precision dosing (MIPD) for tacrolimus and mycophenolic acid in paediatric patients with a kidney disease

Despite the fact that patients can differ greatly from each other, most drugs
are dosed according to a *one-size-fits-all* approach. This approach could
result in risks for undertreatment as well as unnecessary adverse effects
because of substantial between-patient variability in drug pharmacokinetics
(PK). This highlights the necessity of tailoring the drug dose to individual
needs for more precise therapy. In current practice, therapeutic drug
monitoring (TDM) is used for drugs with a narrow therapeutic index, where small
changes in drug concentrations can significantly affect the drug's efficacy and
toxicity. In contrast to regular TDM, model-Informed precision dosing (MIPD)
uses pharmacometric models, simulation, and Bayesian forecasting tools designed
to predict the optimal dose of a drug for a patient, taking individual
demographic and clinical patient characteristics into account. This leads to a
more individualised and precise dose advice. Plenty of studies suggest benefits
of the use of MIPD, however implementation of MIPD in clinical practice is
lagging behind. Therefore, we aim to develop, implement and evaluate MIPD in
clinical practice for different indications, populations and drugs.
In the first project (appendix 1), we will focuss on tacrolimus and
mycoophenolic acid in peadiatric patients with a kidney disease.

Overall objective:To improve the existing drug prescribing and treatment
monitoring process.
Objective appendix 1: To prospectively evaluate the predictive performance of
the MIPD strategy for tacrolimus and mycophenolic acid in paediatric patients
with a kidney disease

Appendix 1:
This is a prospective observational study of MIPD in clinical practice for
kidney disease patients using tacrolimus and mycophenolic acid in Radboudumc.
Dose individualization in these patients using the InsightRX platform is
performed as standard care, meaning that the selected models and drug levels
measured at t=0, t=1 and t=2 hours will be used to calculate the AUC. Based on
the estimated AUC, the pharmacist gives a dose recommendation to the physician,
who can then modify the dosage of mycophenolic acid or tacrolimus. The selected
dose and the measured MPA and tacrolimus concentrations will be used to predict
a future AUC.
In this study an extra AUC will be measured; At the regular follow-up visit,
usually after 1 to 5 months , another 3 samples (t=0, t=1 and t=2 hours) will
be analysed. We will compare the predicted AUC with the newly estimated AUC
(based on the 3 obtained samples) by calculation of the root mean squared error
(RMSE) and the mean prediction error (MPE). In addition, we will calculate in
which percentage of cases the subsequent AUCs lies within the target range. The
target AUC*s are in accordance with the local guidelines.

Appendix 1:
Concerning the single intervention of the study is blood sampling, the risks
are considered as negligible.