Limited sampling strategy for predicting area under the concentration-time curve of mycophenolic acid in adult lung transplant recipients.
OBJECTIVE
To develop limited sampling strategies for estimation of mycophenolic acid exposure (by determining area under the concentration-time curve [AUC]) in lung transplant recipients by using sampling times within 2 hours after drug administration and a maximum of three plasma samples.


METHODS
Prospective, open-label clinical study.


METHODS
Lung transplant clinic in Vancouver, British Columbia, Canada.


METHODS
Nineteen adult (mean age 48.3 yrs) lung transplant recipients who were receiving mycophenolate mofetil therapy along with cyclosporine (9 patients) or tacrolimus (10 patients).


METHODS
Eleven blood samples were collected from each of the 19 patients over 12 hours: immediately before (0 hr) and 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after administration of mycophenolate mofetil.


RESULTS
Mycophenolic acid levels in plasma were determined by a high-performance liquid chromatography-ultraviolet detection method. The 19 patients were randomly divided into index (10 patients) and validation (9 patients) groups. Limited sampling strategies were developed with multiple regression analysis by using data from the index group. Data from the validation group were used to test each strategy. Bias and precision of each limited sampling strategy were determined by calculating the mean prediction error and the root mean square error, respectively. The correlation between AUC and single concentrations was generally poor (r2= 0.18-0.73). Two single-concentration strategies, eight two-concentration strategies, and eight three-concentration strategies matched our criteria. However, the best overall limited sampling strategies (and their predictive performance) were the following: log AUC = 0.241 log C0 + 0.406 log C2 + 1.140 (bias -5.82%, precision 5.97%, r2= 0.828) and log AUC = 0.202 log C0 + 0.411 log C1.5 + 1.09 (bias -5.71%, precision 6.94%, r2= 0.791), where Cx is mycophenolic acid concentration at time x hours.


CONCLUSIONS
Two-concentration limited sampling strategies provided minimally biased and highly precise estimation of mycophenolic acid AUC in lung transplant recipients. These optimal and most clinically feasible limited sampling strategies are based collectively on the number of blood samples required, r2 value, bias, and precision.
Ting
Lillian S L
LS
Faculties of Pharmaceutical Sciences, Vancouver, British Columbia, Canada.
Partovi
Nilufar
N
Levy
Robert D
RD
Riggs
K Wayne
KW
Ensom
Mary H H
MH
D000328:Adult; D019540:Area Under Curve; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid