Pharmacokinetic Modelling and Development of Bayesian Estimators for Therapeutic Drug Monitoring of Mycophenolate Mofetil in Reduced-Intensity Haematopoietic Stem Cell Transplantation

• Published in: Clinical pharmacokinetics 2009-01, Vol.48 (10), p.667-675
• Main Authors: Saint-Marcoux, Franck, Royer, Bernard, Debord, Jean, Larosa, Fabrice, Legrand, Faezeh, Deconinck, Eric, Kantelip, Jean-Pierre, Marquet, Pierre
• Format: Article
• Language: English
• Subjects: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Area Under Curve; Bayes Theorem; Biological and medical sciences; Drug Monitoring; Drug Monitoring - methods; Female; General pharmacology; Health aspects; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Humans; Internal Medicine; Life Sciences; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Theoretical; Mycophenolate mofetil; Mycophenolic Acid; Mycophenolic Acid - administration & dosage; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - blood; Mycophenolic Acid - pharmacokinetics; Original Research Article; Pharmaceutical sciences; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Pilot Projects; Prodrugs; Prodrugs - pharmacokinetics; Transplantation; Young Adult
• ISSN: 0312-5963; 1179-1926
• DOI: 10.2165/11317140-000000000-00000

Background Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical. Objectives To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT. Patients and Methods Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. Results: The ITS approach allowed the development of MAP-BEs based either on ‘double-gamma’ or ‘triplegamma’ models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was s