Population Pharmacokinetics And Bayesian Estimation of Mycophenolate
Mofetil In Patients With Autoimmune Hepatitis
Abstract
Background: Mycophenolate mofetil (MMF) is the most widely used
second-line agent in auto-immune hepatitis (AIH). It is generally
titrated up to patient response and continued for at least two years
following complete liver enzyme normalization. However, in this
maintenance phase individual dose adjustment to reach mycophenolic acid
(MPA) exposure with the best benefit-risk probability may avoid adverse
outcomes. The aim of the present study was to develop population
pharmacokinetic (popPK) models and Maximum A-Posteriori Bayesian
estimators (MAP-BEs) to estimate MPA inter-dose area under the curve
(AUC0-12h) in AIH patients administered MMF using nonlinear mixed effect
modelling. Methods: We analysed 50 MPA PK profiles from 34 different
patients, together with some demographic, clinical, and laboratory test
data. The median number of samples per profile, immediately preceding
and following the morning MMF dose, was 7 [4 – 10]. PopPK modeling
was performed using parametric, top-down, nonlinear mixed effect
modelling with NONMEM 7.3. MAP-BEs were developed based on the the best
popPK model and the best limited sampling strategy (LSS) selected among
several. Results: The pharmacokinetic data were best described by a
2-compartment model, Erlang distribution to describe the absorption
phase, and a proportional error. The best MAP-BE relied on the LSS at
0.33, 1 and 3 hours after mycophenolate mofetil dose administration and
was very accurate (bias=5.6%) and precise (RMSE<20%).
Conclusion: The precise and accurate Bayesian estimator developed in
this study for AIH patients on MMF can be used to improve the
therapeutic management of these patients.