A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients

Abstract

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 x C0 + 1.77 x C2 + 4. 1 x C4 (mean prediction error +/- SD = 0.3 +/- 6.4%, 95% confidence interval=-1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period.

Cyclosporine A monitoring ? how to account for twice and three times daily dosing

“…Because measurement of the total AUC requires repeated blood sampling and is time-consuming and expensive, many surrogates have been developed for AUC determination. These include the 2 h post-dose concentration (C 2 ) monitoring [17,18,19,20] and limited sampling strategies that estimate the absorption phase or the complete AUC for CsA in adults [21,22] and children [23,24,25,26,27].…”

Development and Validation of Limited Sampling Strategies for Estimation of Cyclosporine Area Under the Concentration–Time Curve in Hematopoietic Stem Cell Transplant Patients

“…In our study, distribution of prediction errors or relative prediction errors did not follow either a normal or log-normal distribution; therefore, for assessment of predictive performance of different models, median prediction error and median absolute prediction error were selected as measures of bias and precision, respectively. 14 In reference to the goodness of prediction, as stated by other investigators, 11,22,33,34 prediction errors of 615% or 20% were the most common percentages that were used in clinical practice because this is the deviation from a predefined targeted value that would initiate dosage adjustment. Therefore, a deviation of 615% was used in the present study as a measure of good prediction.…”

Absorption phase cyclosporine (C2�h) monitoring in the first weeks after pediatric renal transplantation

“…These data have not been directly applied to children because there are possible theoretical differences in pharmacokinetics [15]. Retrospective studies from pediatric renal graft recipients have been performed mainly in the stable phase after transplantation and C 1 h [5], C 1.25 h [6], C 2 h [7,8], C 3 h [9], or combinations such as C 2 h and C 6 h [10] have been shown to yield the best correlation with AUC 0-4 h . Trompeter et al [11] recently reported a prospective study with CsA profiles and found a C 2 h of more than 1,500 ng/ml to be significantly superior in preventing rejection.…”

“…Several studies have addressed the best single time point to predict total drug exposure. Different results have been published and C 1 h [5], C 1.25 h [6], C 2 h [7,8], C 3 h [9], or combinations of single time points [10] showed the best correlation. Thirty-two children have been evaluated prospectively in the early transplant period and freedom from rejection was observed with a C 2 h of >1,500 ng/ml [11].…”