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Limited sampling strategy and population pharmacokinetic model of mycophenolic acid in pediatric patients with systemic lupus erythematosus: application of a double gamma absorption model with SAEM algorithm

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Abstract

Introduction

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is widely used in the treatment of systemic lupus erythematosus (SLE). It has been shown that its therapeutic drug monitoring based on the area under the curve (AUC) improves treatment efficacy. MPA exhibits a complex bimodal absorption, and a double gamma distribution model has been already proposed in the past to accurately describe this phenomenon. These previous population pharmacokinetics models (POPPK) have been developed using iterative two stage Bayesian (IT2B) or non-parametric adaptive grid (NPAG) methods. However, non-linear mixed effect (NLME) approaches based on stochastic approximation expectation–maximization (SAEM) algorithms have never been published so far for this particular model. The objectives of this study were (i) to implement the double absorption gamma model in Monolix, (ii) to compare different absorption models to describe the pharmacokinetics of MMF, and (iii) to develop a limited sampling strategy (LSS) to estimate AUC in pediatric SLE patients.

Material and methods

A data splitting of full pharmacokinetic profiles sampled in 67 children extracted either from the expert system ISBA (n = 34) or the hospital Saint Louis (n = 33) was performed into train (75%) and test (25%) sets. A POPPK was developed for MPA in the train set using a NLME and the SAEM algorithm and different absorption models were implemented and compared (first order, transit, or simple and double gamma). The best limited sampling strategy was then determined in the test set using a maximum-a-posteriori Bayesian method to estimate individual PK parameters and AUC based on three blood samples compared to the reference AUC calculated using the trapezoidal rule applied on all samples and performances were assessed in the test set.

Results

Mean patient age and dose was 13 years old (5–18) and 18.1 mg/kg (7.9–47.6), respectively. MPA concentrations (764) from 107 occasions were included in the analysis. A double gamma absorption with a first-order elimination from the central compartment best fitted the data. The optimal LSS with samples at 30 min, 2 h, and 3 h post-dose exhibited good performances in the test set (mean bias − 0.32% and RMSE 21.0%).

Conclusion

The POPPK developed in this study adequately estimated the MPA AUC in pediatric patients with SLE based on three samples. The double absorption gamma model developed with the SAEM algorithm showed very accurate fit and reduced computation time.

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Data availability

Supporting information is available in the additional files and further supporting data is available from the authors on reasonable request.

Code availability

Mlxtran model code is available in supplementary materials.

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Funding

Kévin Koloskoff received funding from the “association nationale recherche technologie” (ANRT) through a “convention industrielle de formation par la recherche” thesis. This research is also supported by Exactcure.  Association Nationale de la Recherche et de la Technologie, 2021/1440.

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Authors and Affiliations

  1. INSERM, University of Limoges, CHU Limoges, P&T, U1248, Limoges, France

    Kévin Koloskoff, Pierre Marquet & Jean-Baptiste Woillard

  2. EXACTCURE, Nice, France

    Kévin Koloskoff, Sylvain Benito, Lucie Chambon & Frédéric Dayan

  3. Department of Pharmacology and Pharmacogenetics, Université Paris Cité, Hôpital Saint-Louis, Paris, France

    Evelyne Jacqz-Aigrain

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  1. Kévin Koloskoff
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  7. Jean-Baptiste Woillard
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Contributions

KK, JBW, and SB contributed to the study conception and design. Data collection was performed by EJA and JBW. Data analysis was performed by KK, LC, and JBW. The first draft of the manuscript was written by KK and JBW, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jean-Baptiste Woillard.

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Koloskoff, K., Benito, S., Chambon, L. et al. Limited sampling strategy and population pharmacokinetic model of mycophenolic acid in pediatric patients with systemic lupus erythematosus: application of a double gamma absorption model with SAEM algorithm. Eur J Clin Pharmacol 80, 83–92 (2024). https://doi.org/10.1007/s00228-023-03587-0

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