title: Development of a predictive limited sampling strategy for estimation of mycophenolic acid area under the concentration time curve in patients receiving concomitant sirolimus or cyclosporine.
abstract: Limited sampling strategies for estimation of the area under the concentration time curve (AUC) for mycophenolic acid (MPA) co-administered with sirolimus (SRL) have not been previously evaluated. The authors developed and validated 68 regression models for estimation of MPA AUC for two groups of patients, one with concomitant SRL (n = 24) and the second with concomitant cyclosporine (n=14), using various combinations of time points between 0 and 4 hours after drug administration. To provide as robust a model as possible, a dataset-splitting method similar to a bootstrap was used. In this method, the dataset was randomly split in half 100 times. Each time, one half of the data was used to estimate the equation coefficients, and the other half was used to test and validate the models. Final models were obtained by calculating the median values of the coefficients. Substantial differences were found in the pharmacokinetics of MPA between these groups. The mean MPA AUC as well as the standard deviation was much greater in the SRL group, 56.4 +/- 23.5 mg.h/L, compared with 30.4 +/- 11.0 mg.h/L in the cyclosporine group (P < 0.001). Mean maximum concentration was also greater in the SRL group: 16.4 +/- 7.7 mg/L versus 11.7 +/- 7.1mg/L (P < 0.005). The second absorption peak in the pharmacokinetic profile, presumed to result from enterohepatic recycling of glucuronide MPA, was observed in 70% of the profiles in the SRL group and in 35% of profiles from the cyclosporine group. Substantial differences in the predictive performance of the regression models, based on the same time points, were observed between the two groups. The best model for the SRL group was based on 0 (trough) and 40 minutes and 4 hour time points with R2, root mean squared error, and predictive performance values of 0.82, 10.0, and 78%, respectively. In the cyclosporine group, the best model was 0 and 40 minutes and 2 hours, with R2, RMSE, and predictive performance values of 0.86, 4.1, and 83%, respectively. The model with 2 hours as the last time point is also recommended for the SRL group for practical reasons, with the above parameters of 0.77, 11.3, and 69%, respectively.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Figurski
authors.forename: Artur
authors.initials: A
authors.lastname: Nawrocki
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
authors.forename: Rene
authors.initials: R
authors.lastname: Bouw
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009173:Mycophenolic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011237:Predictive Value of Tests; D012044:Regression Analysis; D015203:Reproducibility of Results; D020123:Sirolimus / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus