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Renal function and albumin concentration are determinants of mycophenolic acid pharmacokinetics
Author(s) -
Hest R. M.,
Gelder T.,
Vulto A. G.,
Mathot R. A.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.131
Subject(s) - pharmacokinetics , mycophenolic acid , renal function , albumin , chemistry , nonmem , transplantation , creatinine , pharmacology , population , pharmacodynamics , serum albumin , population pharmacokinetics , urology , medicine , biochemistry , environmental health
Purpose Mycophenolic acid (MPA) is an immunosuppressant used in renal transplantation. The compound exhibits considerable inter‐patient pharmacokinetic variability. In this study a population pharmacokinetic model was developed for MPA to assess the relationship between MPA clearance (Cl) and both renal function and albumin concentrations. Methods Data were obtained from a randomised concentration controlled trial, in which 140 patients participated and individual pharmacokinetics were assessed on 9 occasions during a 24 week period. Results A total of 6523 plasma concentration‐time data were simultaneously fitted to a two compartment model with time‐lagged first order absorption using non‐linear mixed effects modelling (NONMEM). Creatinine clearance (CrCl) significantly correlated with MPA Cl (p<0.001). An CrCl increase from 10 to 30 mL/min resulted in a decrease in MPA Cl from 50 L/h to 41 L/h. A further increase to 100 mL/min yielded a Cl of 33 L/h. MPA Cl correlated (p<0.001) with plasma albumin (ALB) as well; an ALB fall from 50 to 30 g/L corresponded with a Cl rise from 19 to 38 L/h. Conclusion Impaired renal function was associated with an increased Cl of MPA, especially with CrCl levels below 30 mL/min. This may be explained by an increase of the unbound fraction. The latter is corroborated by the fact that Cl increases with decreasing plasma albumin concentration. Following renal transplantation changes in graft function and albumin concentration affect MPA disposition and thereby its pharmacodynamics. Clinical Pharmacology & Therapeutics (2004) 75 , P35–P35; doi: 10.1016/j.clpt.2003.11.131