Work

Killing several birds with one stone: A multi‐indication population pharmacokinetic model and Bayesian estimator for enteric‐coated mycophenolate sodium

Year: 2024

Type: article

Abstract: Aims Mycophenolic acid (MPA), the active component of enteric‐coated mycophenolate sodium (EC‐MPS), exhibits highly variable pharmacokinetics. Only a few population pharmacokinetic (popPK) models and Bayesian estimators (MAP‐BE) exist for estimating MPA AUC and all in renal transplantation. This study aimed to develop a popPK model and MAP‐BE for MPA AUC estimation using a limited sampling strategy (LSS) in solid organ transplant (SOT), haematopoietic stem cell (HSC) recipients and patients with autoimmune diseases (AID) on EC‐MPS. Methods Full and sparse MPA pharmacokinetic profiles were extracted from our ISBA system, split into development (75%) and validation (25%) sets. An additional extraction was performed after the modelling process for external validation. Pharmacokinetic parameters were estimated using Monolix® (SAEM algorithm). Several absorption models (first order, transit, gamma) were compared. AUC predicted by MAP‐BE and LSS was compared to the all‐sample MAP‐BE AUC reference using Simulx®. Results We included 153 PK profiles (863 concentration) from 129 patients (116 SOT and HSC, 13 AID), median [min–max] age 45 years [6–80]. A one‐compartment model with double‐gamma absorption and first‐order elimination best fitted the data. The final model included the EC‐MPS indication and inter‐occasion variability on gamma rate constants. Main PK parameters (mean ± SD) were Cl/F = 4.99 ± 2.22 L/h and Vd/F = 12.60 ± 0.08 L. The optimal LSS at 20 min, 2 h and 4 h post‐dose showed good performance in both validation sets (rMPE −2.67% and −4.91%; RMSE 13.55% and 13.47%). Conclusions The double‐gamma absorption model provided an accurate fit. The MAP‐BE offers a tool for EC‐MPS dose individualization in SOT, HSC and AID patients.

Source: British Journal of Clinical Pharmacology

DOI: 10.1111/bcp.16374