Impact of Administration Time Errors on Clearance Estimation in Pharmacokinetic Analyses

This study aimed to comprehensively assess the impact of administration time errors on the estimation of clearance (CL), a key pharmacokinetic (PK) parameter used to predict appropriate maintenance dosing and drug exposure. To identify general principles, we simulated 23 cases of hypothetical compounds with varying CL, volume of distribution (Vd), and elimination half-lives (t_1/2), and assumed administration time errors of 4, 8, and 12 h on the day before the last dose (Day last-1). Substantial underestimation of CL was observed for compounds with t_1/2 values in the approximate range of 2-26 h, with the largest effects seen for relatively short t_1/2 values of 4-5 h. Mean CL underestimation reached 7.1%, 17.7%, and 31.1% for the 4-, 8-, and 12-h timing errors, respectively. A two-compartment analysis using three oral drugs with distinct distribution characteristics and half-lives was performed to examine structural robustness. The results reproduced the core pattern-greater CL underestimation with larger administration time errors and attenuation with longer t_1/2. These findings suggest that the magnitude of CL estimation error is primarily determined by t_1/2, and a 12-h error can result in clinically relevant bias in CL estimation and potentially affect maintenance dose selection.