Limited sampling strategies drawn within 3 hours postdose poorly predict mycophenolic acid area-under-the-curve after
Brenda C M de Winter1, Teun van Gelder, Ron A A Mathot
1Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands. brendadew@hotmail.com
Abstract:
Previous studies predicted that limited sampling strategies (LSS) for estimation of mycophenolic acid (MPA) area-under-the-curve (AUC(0-12)) after ingestion of enteric-coated mycophenolate sodium (EC-MPS) using a clinically feasible sampling scheme may have poor predictive performance. Failure of LSS was thought to be due to the slow absorption of MPA causing late and variable times of maximum MPA concentration and variable predose concentrations. The aim of this study was to formally test the performance of LSS by developing and validating LSS for estimation of MPA AUC(0-12) after EC-MPS administration. Pharmacokinetic data from 109 renal transplant recipients collected during the maintenance period after transplantation were analysed retrospectively. LSS were developed separately for renal transplant patients who concurrently used cyclosporine (n = 79) and for patients not concurrently treated with cyclosporine (n = 30). Data were split into an index and a validation data set. For clinical feasibility reasons, a LSS could consist of a maximum of 3 sampling time points with the latest sample drawn 2 hours after drug administration. LSS with the latest sample drawn 3 hours after drug administration or even later were also tested. The validation of the developed LSS showed that MPA AUC(0-12) for patients concurrently treated with cyclosporine was best estimated by AUC(0-12) (mg x h x L(-1)) = 36.536 + 1.642 x C0.5 + 0.569 x C1.5 + 0.905 x C2 (r2 = 0.33, bias = -1.0 mg x h x L(-1), precision = 24 mg x h x L(-1)), whereas AUC(0-12) [mg x h x L(-1)] = 19.801 + 1.827 x C0.5 + 1.111 x C1 + 1.429 x C2 was the best AUC(0-12) estimator for patients not cotreated with cyclosporine (r2 = 0.31, bias = 0.4 mg x h x L(-1), precision = 14.5 mg x h x L(-1)). Both LSS showed poor precision and overestimation of AUC(0-12) values below the therapeutic window and underestimation of AUC(0-12) values above the therapeutic window of MPA. Using C3 as latest sampling time point improved the fit slightly, but not satisfactory, with r2 still <0.40 and precision still >14.0 mg x h x L(-1). Estimation of MPA AUC(0-12) with LSS for EC-MPS drawn within 2 or 3 hours postdose in renal transplant recipients in the maintenance period is likely to result in biased and imprecise results.
Insights
Limited sampling strategies for mycophenolic acid (MPA) area-under-the-curve (AUC) estimation in renal transplant patients using enteric-coated mycophenolate sodium (EC-MPS) showed poor predictive performance. These methods resulted in biased and imprecise MPA AUC(0-12) estimations, questioning their clinical utility.
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Transplantation Medicine
Background:
- Limited sampling strategies (LSS) for mycophenolic acid (MPA) area-under-the-curve (AUC(0-12)) estimation after enteric-coated mycophenolate sodium (EC-MPS) administration were predicted to have poor performance.
- Slow absorption of MPA, leading to variable peak concentrations and predose levels, was hypothesized to cause LSS failure.
Purpose of the Study:
- To formally test and validate LSS for estimating MPA AUC(0-12) after EC-MPS administration in renal transplant recipients.
- To develop and assess the predictive performance of LSS in patients with and without concurrent cyclosporine use.
Main Methods:
- Retrospective analysis of pharmacokinetic data from 109 renal transplant recipients in the maintenance phase.
- Development and validation of LSS using index and validation datasets, with a maximum of 3 sampling points, latest drawn within 2-3 hours postdose.
- Separate LSS development for patients concurrently using cyclosporine (n=79) and those not (n=30).
Main Results:
- Developed LSS demonstrated poor precision and bias in MPA AUC(0-12) estimation for both patient groups.
- For cyclosporine users, the best LSS model yielded r2=0.33, bias=-1.0, and precision=24. For non-cyclosporine users, r2=0.31, bias=0.4, and precision=14.5.
- Even with the latest sample drawn at 3 hours postdose, LSS performance remained unsatisfactory (r2 <0.40, precision >14.0).
Conclusions:
- LSS for estimating MPA AUC(0-12) after EC-MPS in renal transplant recipients during the maintenance period are likely to produce biased and imprecise results.
- The tested LSS models exhibited overestimation below the therapeutic window and underestimation above it.
- Current clinically feasible LSS are not reliable for accurate MPA AUC(0-12) monitoring in this patient population.
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