Population pharmacokinetics of mycophenolic acid in lung transplant recipients with and without cystic fibrosis

• Published in: European journal of clinical pharmacology Vol. 71; no. 6; pp. 673 - 679
• Main Authors: Wang, Xiao-Xing, Feng, Meihua R., Nguyen, Hugh, Smith, David E., Cibrik, Diane M., Park, Jeong M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2015; Springer Nature B.V
• Subjects: Adult; Aged; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Clinical Trial; Cystic fibrosis; Cystic Fibrosis - metabolism; Female; Graft Rejection - prevention & control; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Lung Transplantation - methods; Lungs; Male; Middle Aged; Models, Biological; Mycophenolic Acid - administration & dosage; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Transplant Recipients; Transplants & implants; Population pharmacokinetics; Cystic fibrosis; Mycophenolic acid; Lung transplant
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-015-1854-7

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 (K a ), 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 (V 2 /F and V 3 /F) in the CF patients would suggest the importance of MPA therapeutic monitoring for this group.