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.
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...
| Published in: | European Journal of Clinical Pharmacology Vol. 80; no. 1; pp. 83 - 93 |
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| Main Authors: | , , , , , , |
| Format: | equations & formulas research tables/charts Journal Article |
| Published: |
Springer Nature
Jan2024
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=174712212&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 174712212 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Jan2024 vid: 80 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 174712212 173216622 174712212 174712212 10.1007/s00228-023-03587-0 174712212 ppf: 83 ppct: 10 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: 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. aug: au: Koloskoff, Kévin Benito, Sylvain Chambon, Lucie Dayan, Frédéric Marquet, Pierre Jacqz-Aigrain, Evelyne Woillard, Jean-Baptiste affil: INSERM, University of Limoges, CHU Limoges, P&T, U1248, Limoges, France sug: subj: Lupus Erythematosus, Systemic Drug Therapy Mycophenolate Mofetil Pharmacokinetics Mycophenolic Acid Pharmacokinetics Absorption Sampling Methods Strategic Planning Models, Theoretical Algorithms Human Child Descriptive Statistics Program Implementation Comparative Studies Adolescence Mycophenolate Mofetil Administration and Dosage Dosage Calculation Population Characteristics Funding Source Child: 6-12 years Adolescent: 13-18 years ab: 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. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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