BACKGROUND: Mycophenolic acid (MPA) shows complex plasma concentration-time profiles, particularly in the immediate (first month) post-transplantation phase for which no relevant pharmacokinetic model has been proposed thus far. OBJECTIVE: The aim of this study was to develop a model to accurately describe the time profile of plasma MPA concentrations after oral administration of mycophenolate mofetil in adult kidney transplant patients, in any post-transplantation period. METHOD: Full interdose pharmacokinetic profiles were collected in 45 adult renal transplant patients who were orally administered mycophenolate mofetil and ciclosporin; 25 patients were de novo transplant patients for whom individual pharmacokinetics were assessed at three post-transplantation periods (days 3, 7 and 30) and 20 patients were stable transplant patients (>3 months post-transplantation). MPA was determined in plasma by liquid chromatography-mass spectrometry. Models combining a single- or double-input (described as single or double gamma distributions) with one- or two-compartments were developed using in-house software and fitted to the individual profiles by nonlinear regression. RESULTS: Visual inspection of the pharmacokinetic profiles showed highly variable absorption profiles and secondary peaks of various intensity. The pharmacokinetic models including a double gamma distribution best fitted these various profiles in the immediate post-transplantation period (mean bias and precision of -0.92% and 20.19%; -1.5% and 18.02%, on day 7 and day 30, respectively), while in the stable post-grafting phase (beyond 3 months), the single- and double-absorption models performed similarly (mean bias and precision of -3.37% and 17.64%; -3.12% and 18.44%, on day 7 and day 30, respectively). CONCLUSION: The proposed pharmacokinetic models adequately describe the concentration-time profiles of MPA in renal transplant patients and could be helpful in the development of tools for MPA monitoring.
BACKGROUND:Mycophenolic acid (MPA) shows complex plasma concentration-time profiles, particularly in the immediate (first month) post-transplantation phase for which no relevant pharmacokinetic model has been proposed thus far. OBJECTIVE: The aim of this study was to develop a model to accurately describe the time profile of plasma MPA concentrations after oral administration of mycophenolate mofetil in adult kidney transplant patients, in any post-transplantation period. METHOD: Full interdose pharmacokinetic profiles were collected in 45 adult renal transplant patients who were orally administered mycophenolate mofetil and ciclosporin; 25 patients were de novo transplant patients for whom individual pharmacokinetics were assessed at three post-transplantation periods (days 3, 7 and 30) and 20 patients were stable transplant patients (>3 months post-transplantation). MPA was determined in plasma by liquid chromatography-mass spectrometry. Models combining a single- or double-input (described as single or double gamma distributions) with one- or two-compartments were developed using in-house software and fitted to the individual profiles by nonlinear regression. RESULTS: Visual inspection of the pharmacokinetic profiles showed highly variable absorption profiles and secondary peaks of various intensity. The pharmacokinetic models including a double gamma distribution best fitted these various profiles in the immediate post-transplantation period (mean bias and precision of -0.92% and 20.19%; -1.5% and 18.02%, on day 7 and day 30, respectively), while in the stable post-grafting phase (beyond 3 months), the single- and double-absorption models performed similarly (mean bias and precision of -3.37% and 17.64%; -3.12% and 18.44%, on day 7 and day 30, respectively). CONCLUSION: The proposed pharmacokinetic models adequately describe the concentration-time profiles of MPA in renal transplant patients and could be helpful in the development of tools for MPA monitoring.
Authors: J Debord; E Risco; M Harel; Y Le Meur; M Büchler; G Lachâtre; C Le Guellec; P Marquet Journal: Clin Pharmacokinet Date: 2001 Impact factor: 6.447
Authors: M Shipkova; V W Armstrong; D Kuypers; F Perner; V Fabrizi; H Holzer; E Wieland; M Oellerich Journal: Ther Drug Monit Date: 2001-12 Impact factor: 3.681
Authors: L T Weber; T Lamersdorf; M Shipkova; P D Niedmann; M Wiesel; L B Zimmerhackl; A Staskewitz; E Schütz; O Mehls; M Oellerich; V W Armstrong; B Tönshoff Journal: Ther Drug Monit Date: 1999-10 Impact factor: 3.681
Authors: M D Hale; A J Nicholls; R E Bullingham; R Hené; A Hoitsma; J P Squifflet; W Weimar; Y Vanrenterghem; F J Van de Woude; G A Verpooten Journal: Clin Pharmacol Ther Date: 1998-12 Impact factor: 6.875