PMID- 37897528
OWN - NLM
STAT- MEDLINE
DCOM- 20240111
LR  - 20240116
IS  - 1432-1041 (Electronic)
IS  - 0031-6970 (Linking)
VI  - 80
IP  - 1
DP  - 2024 Jan
TI  - 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.
PG  - 83-92
LID - 10.1007/s00228-023-03587-0 [doi]
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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, 
      part of Springer Nature.
FAU - Koloskoff, Kevin
AU  - Koloskoff K
AD  - INSERM, University of Limoges, CHU Limoges, P&T, U1248, Limoges, France.
AD  - EXACTCURE, Nice, France.
FAU - Benito, Sylvain
AU  - Benito S
AD  - EXACTCURE, Nice, France.
FAU - Chambon, Lucie
AU  - Chambon L
AD  - EXACTCURE, Nice, France.
FAU - Dayan, Frederic
AU  - Dayan F
AD  - EXACTCURE, Nice, France.
FAU - Marquet, Pierre
AU  - Marquet P
AD  - INSERM, University of Limoges, CHU Limoges, P&T, U1248, Limoges, France.
FAU - Jacqz-Aigrain, Evelyne
AU  - Jacqz-Aigrain E
AD  - Department of Pharmacology and Pharmacogenetics, Universite Paris Cite, Hopital 
      Saint-Louis, Paris, France.
FAU - Woillard, Jean-Baptiste
AU  - Woillard JB
AUID- ORCID: 0000-0003-1695-0695
AD  - INSERM, University of Limoges, CHU Limoges, P&T, U1248, Limoges, France. 
      jean-baptiste.woillard@unilim.fr.
LA  - eng
GR  - 2021/1440/Association Nationale de la Recherche et de la Technologie/
PT  - Journal Article
DEP - 20231028
PL  - Germany
TA  - Eur J Clin Pharmacol
JT  - European journal of clinical pharmacology
JID - 1256165
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - 0 (Immunosuppressive Agents)
SB  - IM
MH  - Humans
MH  - Child
MH  - Adolescent
MH  - *Mycophenolic Acid
MH  - Immunosuppressive Agents/pharmacokinetics
MH  - Bayes Theorem
MH  - *Lupus Erythematosus, Systemic/drug therapy
MH  - Area Under Curve
MH  - Seizures/drug therapy
MH  - Algorithms
OTO - NOTNLM
OT  - Double absorption model
OT  - Mycophenolic acid
OT  - Population pharmacokinetics
OT  - SAEM
OT  - Systemic lupus erythematosus
EDAT- 2023/10/29 06:43
MHDA- 2024/01/11 07:42
CRDT- 2023/10/28 11:04
PHST- 2023/08/04 00:00 [received]
PHST- 2023/10/21 00:00 [accepted]
PHST- 2024/01/11 07:42 [medline]
PHST- 2023/10/29 06:43 [pubmed]
PHST- 2023/10/28 11:04 [entrez]
AID - 10.1007/s00228-023-03587-0 [pii]
AID - 10.1007/s00228-023-03587-0 [doi]
PST - ppublish
SO  - Eur J Clin Pharmacol. 2024 Jan;80(1):83-92. doi: 10.1007/s00228-023-03587-0. Epub 
      2023 Oct 28.