Xiao-Xing Wang1, Meihua R Feng2, Hugh Nguyen3, David E Smith1, Diane M Cibrik4, Jeong M Park5. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI, 48109, USA. 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI, 48109, USA. fengmr@med.umich.edu. 3. College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA. 4. Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA. 5. Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
Abstract
PURPOSE: The objective of this work was to characterize and compare the population pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF) as an immunosuppressant. METHODS: Three separate 12-h PK visits were conducted for lung transplant patients with or without CF following repeated MPA treatment with at least a 2-week break between the visits. A population PK model was developed using nonlinear mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors and time dependence of apparent oral clearance (CL/F) were assessed. RESULTS: For both CF and NCF patients, MPA serum concentration-time profiles were best described by a two-compartment PK model with first-order absorption. CF patients had a slower absorption rate (Ka), and elevated CL/F and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of body weight and CF disease to MPA CL/F, and both were included in the final model as covariates. CONCLUSIONS: The population PK model developed from our study successfully characterizes the absorption, distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution (V2/F and V3/F) in the CF patients would suggest the importance of MPA therapeutic monitoring for this group.
PURPOSE: The objective of this work was to characterize and compare the population pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF) as an immunosuppressant. METHODS: Three separate 12-h PK visits were conducted for lung transplant patients with or without CF following repeated MPA treatment with at least a 2-week break between the visits. A population PK model was developed using nonlinear mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors and time dependence of apparent oral clearance (CL/F) were assessed. RESULTS: For both CF and NCF patients, MPA serum concentration-time profiles were best described by a two-compartment PK model with first-order absorption. CFpatients had a slower absorption rate (Ka), and elevated CL/F and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of body weight and CF disease to MPA CL/F, and both were included in the final model as covariates. CONCLUSIONS: The population PK model developed from our study successfully characterizes the absorption, distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution (V2/F and V3/F) in the CFpatients would suggest the importance of MPA therapeutic monitoring for this group.
Authors: Leslie M Shaw; Michal Figurski; Michael C Milone; Jennifer Trofe; Roy D Bloom Journal: Clin J Am Soc Nephrol Date: 2007-08-16 Impact factor: 8.237
Authors: Jason D Christie; Leah B Edwards; Anna Y Kucheryavaya; Christian Benden; Anne I Dipchand; Fabienne Dobbels; Richard Kirk; Axel O Rahmel; Josef Stehlik; Marshall I Hertz Journal: J Heart Lung Transplant Date: 2012-10 Impact factor: 10.247
Authors: Wolfgang Arns; Diane M Cibrik; Rowan G Walker; Georges Mourad; Klemens Budde; Edgar A Mueller; Flavio Vincenti Journal: Transplantation Date: 2006-10-27 Impact factor: 4.939
Authors: Lillian S L Ting; Nilufar Partovi; Robert D Levy; K Wayne Riggs; Mary H H Ensom Journal: Ann Pharmacother Date: 2006-08-01 Impact factor: 3.154
Authors: Brenda C M de Winter; Teun van Gelder; Ferdi Sombogaard; Leslie M Shaw; Reinier M van Hest; Ron A A Mathot Journal: J Pharmacokinet Pharmacodyn Date: 2009-11-11 Impact factor: 2.745