Leave-one-out Procedure in the Validation of Elimination Rate Constant Analysis

Abstract

Many registration agencies and other organizations define how to calculate the elimination rate constant (k_el) value. No validation procedures have been introduced to verify the correct selection of the concentration-time (C–T) points used for the k_el calculation. The purpose of this paper is to discover whether k_el analysis can be subjected to the condensed validation procedure and what acceptance criteria should be adopted for such a procedure. For the analysis, data collected during bioequivalence studies of 4 drugs were selected, including 2 highly lipophilic drugs (itraconazole, atorvastatin) and 2 weakly lipophilic drugs (trimetazidine, perindopril). Pharmacokinetic calculations were performed with the use of WinNonlin Professional v 5.3. Internal validation of the k_el analysis using leave-one-out cross-validation was performed. The present analysis proves that the C–T selection process for the k_el calculations cannot be automated. In each of the analysed data series there were such C–T sequences that did not meet even one of the validation criteria. This paper proposes 3 validation criteria which need to be met in order to confirm the optimal selection of C–T data to calculate k_el: Q ²≥0.6, R²≥ 0.85, Q ²–R²<0.3, were Q ² – squared cross-validated correlation coefficient, R² – coefficient of determination). Application of the validation procedure for the k_el analysis under discussion proves the accuracy of the calculations, even if repeated k_el analysis is based on a different sequence of points in the elimination phase.

Key words

leave one out - validation - elimination rate - GLP

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