Statistical Methods for Assessing Stability of Compounds in Whole Blood for Clinical Bioanalysis
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Drug Informarion J o u m l , Vol. 35. pp. 1261-1270. 2001 Printed in the USA. All rights reserved.
Copyright 0 2001 Drug Information Association Inc.
STATISTICAL METHODS FOR ASSESSING STABILITY OF COMPOUNDS IN WHOLE BLOOD FOR CLINICAL BIOANALYSIS ROBERTKRINGLEAND DAVIDHOFFMAN heclinical and Research Statistics
JOHN NEWTONAND REGINABURTON Clinical Metabolism and Pharmacokinetics Sanofi-Synthelabo Research Division, Malvem, Pennsylvania
The objective of a blood stability study is to assess the stability of a compound in whole blood after storage in collection vessels at room temperature for two to four hours for samples drawn in the clinic, and for six to eight hours for samples drawn elsewhere and transported to the clinic, in order to develop proper sample handling recommendations for clinical studies. Common practice is to transfer blood from a spiked whole blood pool into collection vessels at 24, 3, and 0 hours prior to analysis. A loss of 15% for a specific proportion of replicates, or for the observed mean, compared to the 0 hour control mean, is often used to decide whether there is any clinically relevant instability at 3 and 24 hours. This procedure is easy to implement, and meets Food and Drug Administration requirements, but it has unknown and uncontrolled risks of incorrect decisions uailing to detect a truly unstable compound, or falsely concluding instability). Investigations were conducted to evaluate various data analysis and decision procedures that control these risks of incorrect decisions, and to optimize the study design and sample size. The recommended data analysis procedure is a linear regression analysis, with an equivalence test for comparing predicted mean concentrations at time = x hours versus the zero hour control, with f 1 5 % specification limits. A study design with n = 9 replicates at 0, 3, 6, and 24 hours yields suflcient power for demonstrating stability. Key Words: Stability; Equivalence; Linear regression; Fieller’s method
INTRODUCTION
THE OBJECTIVE OF A study is to assess the stability of a compound in whole blood after storage in collection vessels at room temperature. In a typical clinical study, it may be expected that drawn blood samples will sit for a short time prior
Reprint address: Robert Kringle, heclinical and Research Statistics, Sanofi-Synthelabo Research Division, 25 Great V d e y Parkway, Malvern. PA 19355. E-mail: Robert.Knngle~sanofi-synthelabo.com.
to analysis, typically for no more than two or three hours. In unusual circumstances, samples may have to be transported to another site for analysis. Thus, six- to eighthour stability may be of importance. Blood stability studies are undertaken to determine the proper handling recommendations for the drawn blood samples in clinical studies. A typical blood stability study consists of transferring samples from a spiked whole blood pool into collection vessels at 24 hours, 3 hours, and 0 hours prior to analysis. All samples are then assayed in a single run,
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