1. Clin Pharmacokinet. 2009;48(11):745-58. doi: 10.2165/11318060-000000000-00000.

Limited sampling models and Bayesian estimation for mycophenolic acid area under 
the curve prediction in stable renal transplant patients co-medicated with
ciclosporin or sirolimus.

Musuamba FT, Rousseau A, Bosmans JL, Senessael JJ, Cumps J, Marquet P, Wallemacq 
P, Verbeeck RK.

School of Pharmacy, Faculty of Medicine, Université Catholique de Louvain,
Brussels, Belgium. flora.musuamba@uclouvain.be

BACKGROUND AND OBJECTIVE: Mycophenolate mofetil is a prodrug of mycophenolic acid
(MPA), an immunosuppressive agent used in combination with corticosteroids and
calcineurin inhibitors or sirolimus for the prevention of acute rejection after
solid organ transplantation. Although MPA has a rather narrow therapeutic window 
and its pharmacokinetics show considerable intra- and interindividual
variability, dosing guidelines recommend a standard dosage regimen of 0.5-1.0 g
twice daily in adult renal, liver and cardiac transplant recipients. The main
objective of the present study was to develop a method to predict the MPA area
under the plasma concentration-time curve during one 12-hour dosing interval
(AUC(12)) by using multiple linear regression models and maximum a posteriori
(MAP) Bayesian estimation methods in patients co-medicated with ciclosporin or
sirolimus, aiming to individualize the dosage regimen of mycophenolate mofetil.
PATIENTS AND METHODS: Pharmacokinetic profiles of MPA and mycophenolic acid
glucuronide (MPAG), the main metabolite of MPA, were obtained from 40 stable
adult renal allograft recipients on three different occasions: the day before
switching from ciclosporin to sirolimus co-medication (+/-7.4 months
post-transplantation; period I) and at 60 days and 270 days after the switch
(periods II and III). Blood samples for determination of MPA and MPAG
concentrations in plasma were taken at 0 hours (pre-dose) and at 0.33, 0.66,
1.25, 2, 4, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. The MPA
AUC(12) was calculated by the trapezoidal method (the observed AUC(12)). Patients
were randomly divided into (i) a model-building test group (n = 27); and (ii) a
model-validation group (n = 13). Multiple linear regression models were
developed, based on three sampling times after drug administration. Subsequently,
a population pharmacokinetic model describing MPA and MPAG plasma concentrations 
was developed using nonlinear mixed-effects modelling and a Bayesian estimator
based on the population pharmacokinetic model was used to predict the MPA AUC(12)
based on three sampling times taken within 2 hours following dosing. RESULTS:
Fifty-two percent of the observed AUC(12) values (three periods) in the 40
patients receiving a fixed dose of mycophenolate mofetil 750 mg twice daily were 
outside the recommended therapeutic range (30-60 microg x h/mL). The failure of
the standard dose to yield an AUC(12) value within the therapeutic range was
especially pronounced during the first study period. Of the multiple linear
regression models that were tested, the equation based on the 0-hour (pre-dose), 
0.66- and 2-hour sampling times showed the best predictive performance in the
validation group: r2 = 0.79, relative root mean square error (rRMSE) = 14% and
mean relative prediction error (MRPE) = 0.9%. The pharmacokinetics of MPA and
MPAG were best described by a two-compartment model with first-order absorption
and elimination for MPA, plus a compartment for MPAG, also including a
gastrointestinal compartment and enterohepatic cycling in the case of sirolimus
co-medication. The ratio of aminotransferase liver enzymes (AST and ALT) and the 
glomerular filtration rate significantly influenced MPA glucuronidation and MPAG 
renal excretion, respectively. Bayesian estimation of the MPA AUC(12) based on
0-, 1.25- and 2-hour sampling times predicted the observed AUC(12) values of the 
patients in the validation group, with the following predictive performance
characteristics: r2 = 0.93, rRMSE = 12.4% and MRPE = -0.4%. CONCLUSION: Use of
the developed multiple linear regression equation and Bayesian estimator, both
based on only three blood sampling times within 2 hours following a dose of
mycophenolate mofetil, allowed an accurate prediction of a patient's MPA AUC(12) 
for therapeutic drug monitoring and dose individualization. These findings should
be validated in a randomized prospective trial.

PMID: 19817503 [PubMed - indexed for MEDLINE]