Astrid Heida 1, Rob Aarnoutse 1, Elisabeth Cornelissen 2, Brenda de Winter 3, Ron Keizer 4, R ter Heine 1, N Jager 1
1 Department of Pharmacy, Pharmacology and Toxicology, Radboud Institute for Medical Innovation, Radboud university medical center (Nijmegen, The Netherlands), 2 Department of Pediatric Nephrology, Radboud university medical center, Amalia Children's Hospital (Nijmegen, The Netherlands), 3 Department of Hospital Pharmacy, Erasmus University Medical Center (Rotterdam, The Netherlands), 4 Insight Rx (San Francisco, USA)
Objectives
Mycophenolic acid (MPA) and tacrolimus are frequently used in kidney diseases like kidney transplantation and nephrotic syndrome. The use of pharmacokinetic (PK) compartmental models to optimize dosing based on therapeutic drug monitoring (TDM) data is referred to as model-informed precision dosing (MIPD). A key advantage of MIPD is its flexibility: drug exposure can be estimated using any number of samples collected at any time. In addition, population characteristics and patient characteristics are considered when estimating exposure. To optimize treatment with MPA and tacrolimus in children with a kidney disease, we evaluated MIPD for both drugs.
Methods
The evaluation followed a structured five-step approach: (1) Selection of population PK models, (2) Evaluation of the predictive performance of these models with retrospective real-world patient data, (3) Evaluation of limited sampling strategies, (4) Implementation of the best suitable models in a MIPD platform (InsightRX Nova), (5) Prospective evaluation of long-term predictive performance by predicting an area under the concentration time curve (AUC0-12h) corrected for hematocrit (for tacrolimus) at a next occasion, three months later. Predictive performance was evaluated using bias and imprecision. Acceptable bias and imprecision were defined as a mean prediction error (MPE) and a normalized root mean square error (NRMSE) of less than 25%.
Results
The PK model of Heida et al. was selected for MPA and the PK model of Schijvens et al. was used for tacrolimus.[1, 2]. A 3‑point sampling schedule at 0, 1, and 2 hours post‑dose was deemed feasible and accurate for both drugs to predict the AUC0-12h yielding a MPE and NRMSE of 0.12 (95% confidence interval (CI): −0.32-0.56)% and 21.0 (95% CI: 7.1-34.8)% for MPA, and 0.19 (95% CI: 0.027-0.35)% and 7.79 (95% CI: 3.0-12.6)% for tacrolimus. This strategy was subsequently evaluated prospectively. In the prospective study, MIPD was implemented using the InsightRX nova platform in 29 pediatric patients requiring AUC0-12h monitoring for a kidney disease. Substantial intra-individual variability limited prediction of the AUC0-12h three months later (MPE:15.4(95% CI:14.4-16.4)%, NRMSE: 48.6(95% CI:18.2-79.0)% for MPA, and 64.2(95% CI: 59.7-68.7)% and 210.1(95% CI: 37.1- 383.1)% for tacrolimus).
For MPA, target attainment increased from 59% at the first occasion to 79% at the second occasion. In contrast, target attainment for tacrolimus declined from 71% at the first occasion to 53% at the follow up three months later. The high unexplained intraindividual variability suggested that frequent AUC0-12h monitoring remains necessary to ensure therapeutic exposure.
Conclusions
Overall, this fit-for-purpose evaluation shows that limited sampling strategies can be successfully applied for estimation of current exposure, with similar sampling times for mycophenolic acid and tacrolimus, thereby supporting broader adoption of MIPD in routine clinical care. However, the substantial intra individual variability observed over time makes long term prediction more challenging, emphasizing the need for frequent AUC₀₋₁₂h monitoring to maintain therapeutic exposure.
References:
1. Heida A, Jager NGL, Aarnoutse RE, de Winter BCM, de Jong H, Keizer RJ, et al. Model-informed dose optimization of mycophenolic acid in pediatric kidney transplant patients. Eur J Clin Pharmacol. 2024;80(11):1761-71.
2. Schijvens AM, de Wildt SN, Cornelissen EAM, van Hesteren FHS, Schreuder MF, Ter Heine R. Low Bioavailability of Oral Tacrolimus Suspension in Pediatric Kidney Transplant Patients. Clin Pharmacokinet. 2020;59(11):1483-5.
Reference: PAGE 34 (2026) Abstr 11965 [www.page-meeting.org/?abstract=11965]
Poster: Clinical Applications