Bias in the Wagner-Nelson estimate of the fraction of drug absorbed

Abstract

Purpose: To examine and quantify bias in the Wagner-Nelson estimate of the fraction of drug absorbed resulting from the estimation error of the elimination rate constant (k), measurement error of the drug concentration, and the truncation error in the area under the curve.

Methods: Bias in the Wagner-Nelson estimate was derived as a function of post-dosing time (t), k, ratio of absorption rate constant to k (r), and the coefficient of variation for estimates of k (CVk), or CV% for the observed concentration, by assuming a one-compartment model and using an independent estimate of k. The derived functions were used for evaluating the bias with r = 0.5, 3, or 6; k = 0.1 or 0.2; CV, = 0.2 or 0.4; and CV, =0.2 or 0.4; for t = 0 to 30 or 60.

Results: Estimation error of k resulted in an upward bias in the Wagner-Nelson estimate that could lead to the estimate of the fraction absorbed being greater than unity. The bias resulting from the estimation error of k inflates the fraction of absorption vs. time profiles mainly in the early post-dosing period. The magnitude of the bias in the Wagner-Nelson estimate resulting from estimation error of k was mainly determined by CV,. The bias in the Wagner-Nelson estimate resulting from to estimation error in k can be dramatically reduced by use of the mean of several independent estimates of k, as in studies for development of an in vivo-in vitro correlation. The truncation error in the area under the curve can introduce a negative bias in the Wagner-Nelson estimate. This can partially offset the bias resulting from estimation error of k in the early post-dosing period. Measurement error of concentration does not introduce bias in the Wagner-Nelson estimate.

Conclusions: Estimation error of k results in an upward bias in the Wagner-Nelson estimate, mainly in the early drug absorption phase. The truncation error in AUC can result in a downward bias, which may partially offset the upward bias due to estimation error of k in the early absorption phase. Measurement error of concentration does not introduce bias. The joint effect of estimation error of k and truncation error in AUC can result in a non-monotonic fraction-of-drug-absorbed-vs-time profile. However, only estimation error of k can lead to the Wagner-Nelson estimate of fraction of drug absorbed greater than unity.