Year: 2025
Type: article
Abstract: ABSTRACT 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.
DOI: 10.1111/cts.70448
Authors: Katsukuni Fujimoto, Kazuhiko Asari, Kiyoshi Mihara
Institutions: Musashino University, MSD K.K. (Japan)
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,630
OpenAlex ID: W4417432012