Population pharmacokinetics of mycophenolic acid : a comparison between enteric-coated mycophenolate sodium and mycophenolate mofetil in renal transplant recipients.
OBJECTIVE
The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).


METHODS
MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM). A two-compartment model with first-order absorption and elimination was used to describe the data.


RESULTS
No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h(-1) and 4.1 h(-1) (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (t(lag)) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the t(lag) values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning t(lag) following EC-MPS administration was significantly different from both the t(lag) following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the t(lag) following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the t(lag) was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r(2) = 0.02) than in MMF-treated patients (r(2) = 0.48).


CONCLUSIONS
Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the t(lag) varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.
de Winter
Brenda C M
BC
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands. b.dewinter@erasmusmc.nl
van Gelder
Teun
T
Glander
Petra
P
Cattaneo
Dario
D
Tedesco-Silva
Helio
H
Neumann
Irmgard
I
Hilbrands
Luuk
L
van Hest
Reinier M
RM
Pescovitz
Mark D
MD
Budde
Klemens
K
Mathot
Ron A A
RA
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000465:Algorithms; D019540:Area Under Curve; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D012984:Software; D013608:Tablets, Enteric-Coated; D013997:Time Factors
D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid