A limited sampling strategy for estimating mycophenolic acid area under the curve in adult heart transplant patients treated with concomitant cyclosporine.
OBJECTIVE
Heart transplantation studies have shown a relationship between the mycophenolic acid area under the curve (AUC) 0-12 h (MPA AUC(0-12h)) values and risk of acute rejection episodes and fewer side-effects in patient receiving cyclosporine during the first year post-transplant. However, measurement of full AUC is costly and time consuming and in this case it is an impractical approach to drug monitoring. Therefore, the authors describe a limited sampling strategy to estimate the MPA AUC(0-12h) value in adult heart transplant recipients.


METHODS
Ninety MPA pharmacokinetic (PK) profiles were studied. The samples were collected immediately before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12 h after the morning dose of mycophenolate mofetil (MMF) following an overnight fast. PK profiles were determined at 6-8 weeks, 6, 12 months and more than 1 year after transplantation. Using stepwise multiple linear regression analysis a sampling strategy from 60 of PK profiles was obtained and next the bias and precision of the model were evaluated in another 30 PK profiles.


RESULTS
The three-point model using C(0.5h), C(1h), C(2h) was found to be superior to all other models tested (r(2) = 0.841). The regression equation for AUC estimation which gave the best fit to this model is: 9.69 + 0.63C(0.5) + 0.61C(1) + 2.20C(2). Using that model 63 of the 90 (70%) full AUC values were estimated within 15% of their actual value. For the best-fit model, the mean prediction error was 3.2%, with 95% confidence intervals for prediction error to range from -42.2% to 40.3%. All other models which use one, two or three time-points over the first 2 h are poorer predictors of the full AUC than the model above.


CONCLUSIONS
The proposed three time-point equation to estimate AUC will be helpful in optimizing immunosuppressive therapy in heart transplantation.
Pawinski
T
T
Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland. tompaw@farm.amwaw.edu.pl
Kunicki
P K
PK
Sobieszczanska-Malek
M
M
Gralak
B
B
Szlaska
I
I
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D012044:Regression Analysis; D055815:Young Adult
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid