Efthymios Neroutsos, Georgia Valsami, Aris Dokoumetzidis, J.N. Boletis, S. Marinaki, P. Macheras
1Laboratory of Biopharmaceutics-Pharmacokinetics, Department of Pharmaceutical Technology, School of Pharmacy, National and Kapodistrian University of Athens, Greece; 2Nephrology Department and Renal Transplantation Unit, Laiko Hospital National and Kapodistrian University of Athens, Greece.
Objectives: To develop a population pharmacokinetic (PK) model Mycophenolic acid (MPA) after administration of Mycophenolate Mofetil (MMF) in kidney transplant patients and patients with nephritis caused by lupus erythematosus (LE).
Methods: The study consisted of n=93 patients and all patients were receiving daily MMF doses prior to study participation. MMF doses were 500 mg, 1 g and 1.50 g. Blood samples for MPA determination were collected at 0h (pre dose) 0.5h, 2h and 4h after commencement and were assayed by an HPLC method. After the development of the basic model covariates were screened. The final PK model was validated using nonparametric bootstrapping and a visual predictive check (VPC). Plasma concentration-time data of MPA were analyzed using NONMEM version 7.3.
Results: The final model was a two compartment model with first order absorption and proportional error, with interindividual variability on clearance. Body weight was identified as covariate of clearance. Final model parameter values were CL/F=11.3 L/h, V2/F=11.2 L, Q/F=13.6 L/h, ka=1.58 h-1 and V3/F was fixed to 300 L as reported in literature [1] with IIV of clearance 40.7%. Goodness of fit assessment using diagnostic plots was considered reasonable. Internal validation by VPC and bootstrap resulted that the model is robust and describes well the data including the observed variability.
Conclusions: A preliminary PopPK model for MPA after administration of MMF was developed, that is intended to serve as a prior information for the Bayesian Individualization of MPA levels in Greek hospitals. The model will be enriched with more patients including also patients receiving MPA after renal transplantation.
References:
[1]. Ms Brenda C. M. de Winter, Teun van Gelder, Petra Glander, Dario Cattaneo, Helio Tedesco-Silva, Irmgard Neumann, Luuk Hilbrands, Reinier M. van Hest, Mark D. Pescovitz, Klemens Budde, Ron A. A. Mathot., Clinical Pharmacokinetics, December 2008, Volume 47, Issue 12, pp 827-838
Reference: PAGE 24 (2015) Abstr 3602 [www.page-meeting.org/?abstract=3602]
Poster: Drug/Disease modeling - Other topics