Population pharmacokinetics and Bayesian estimators for intravenous mycophenolate mofetil in haematopoietic stem cell transplant patients

Aims Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced‐intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft‐versus‐host disease. The aims of this study were to develop...

Full description

Saved in:
Bibliographic Details
Published in:British journal of clinical pharmacology 2020-08, Vol.86 (8), p.1550-1559
Main Authors: Labriffe, Marc, Vaidie, Julien, Monchaud, Caroline, Debord, Jean, Turlure, Pascal, Girault, Stephane, Marquet, Pierre, Woillard, Jean‐Baptiste
Format: Article
Language:English
Subjects:
hematopoietic stem cell transplantation
ITSIM
mycophenolic acid
Original
Pmetrics
population pharmacokinetics modelling
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aims Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced‐intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft‐versus‐host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies to allow for individual dose adjustment of intravenous mycophenolate mofetil administered by infusion in haematopoietic stem cell transplant patients. Methods Sixty‐three MPA concentration–time profiles (median [min–max] = 6 [4–7] samples) were collected from 34 HCT recipients transplanted for 14 (1–45) days and administered IV MMF every 8 hours, concomitantly with cyclosporine. The database was split into development (75%) and validation (25%) datasets. Pharmacokinetic models characterized by a single compartment with first‐order elimination, combined with two gamma distributions to describe the transformation of MMF into mycophenolic acid, were developed using in parallel nonparametric (Pmetrics) and parametric (ITSIM) approaches. The performances of the models and the derived Bayesian estimators were evaluated in the validation set. Results The best limited sampling strategy led to a bias (min, max), root mean square error between observed and modeled interdose areas under the curve in the validation dataset of −11.72% (−31.08%, 5.00%), 14.9% for ITSIM and −2.21% (−23.40%, 30.01%), 12.4% for Pmetrics with three samples collected at 0.33, 2 and 3 hours post dosing. Conclusion Population pharmacokinetic models and Bayesian estimators for IV MMF in HCT have been developed and are now available online (https://pharmaco.chu-limoges.fr) for individual dose adjustment based on the interdose area under the curve.
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.14261