Authors: de Winter, Brenda C.M.¹; van Gelder, Teun; Glander, Petra²; Cattaneo, Dario³; Tedesco-Silva, Helio⁴; Neumann, Irmgard⁵; Hilbrands, Luuk⁶; van Hest, Reinier M.¹; Pescovitz, Mark D.; Budde, Klemens²; Mathot, Ron A.A.¹

Source: Clinical Pharmacokinetics, Volume 47, Number 12, 2008 , pp. 827-838(12)

Publisher: Adis International

Abstract:

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 (r² = 0.02) than in MMF-treated patients (r² = 0.48).

Conclusion: 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.

Keywords: Comparative pharmacokinetics; Immunosuppressants; Mycophenolate mofetil; Mycophenolate sodium; Mycophenolic acid; Population pharmacokinetics; Renal transplant

Document Type: Research article

Affiliations: 1: 1 Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands 2: 3 Department of Internal Medicine - Nephrology, Universitätsklinikum Charité Campus Mitte, Humboldt University, Berlin, Germany 3: 4 Center for Research on Organ Transplantation, Mario Negri Institute for Pharmacological Research, Bergamo, Italy 4: 5 Hospital do Rim e Hipertensao, Universidade Federal de Sao Paulo, Sao Paulo, Brazil 5: 6 Department of Nephrology, Wilhelminenspital, Vienna, Austria 6: 7 Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Publication date: 2008-01-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Pharmacology
• By this author: de Winter, Brenda C.M. ;  van Gelder, Teun ;  Glander, Petra ;  Cattaneo, Dario ;  Tedesco-Silva, Helio ;  Neumann, Irmgard ;  Hilbrands, Luuk ;  van Hest, Reinier M. ;  Pescovitz, Mark D. ;  Budde, Klemens ;  Mathot, Ron A.A.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers