An exploration on retro-construction of plasma drug concentration-time curves from corresponding urine excretion data and single-point plasma concentrations using a simplified and idealized method

Guanglu Li; Wenpeng Zhang; Meng Zhang; Jiamin Xu; Guanghua Zhu; Jinglai Li; Huan Luo; Xiaomei Zhuang; Quanjun Wang; Tianhong Zhang

doi:10.21037/tp-22-505

An exploration on retro-construction of plasma drug concentration-time curves from corresponding urine excretion data and single-point plasma concentrations using a simplified and idealized method

Transl Pediatr. 2023 May 30;12(5):845-860. doi: 10.21037/tp-22-505. Epub 2023 Apr 20.

Authors

Guanglu Li^#¹, Wenpeng Zhang^#¹, Meng Zhang^#², Jiamin Xu², Guanghua Zhu², Jinglai Li³, Huan Luo³, Xiaomei Zhuang¹, Quanjun Wang¹, Tianhong Zhang^{1

3}

Affiliations

¹ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
² Department of Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
³ Guoke Excellence (Beijing) Medicine Technology Research Co., Ltd., Beijing, China.

^# Contributed equally.

Abstract

Background: Despite the availability of various tools of modeling and simulation, clinical pediatric pharmacokinetic (PK) studies remain far less efficient than those on adults due to ethical constraints. One of the optimal solutions is to substitute urine to blood sampling based on explicit mathematic relationships between them. However, this idea is limited by three main knowledge gaps associated with urine data, i.e., complicated excretion equations with excessive parameters, insufficient frequency that is hard to fit, and the mere expression of amounts with no in vivo distribution volume information involved.

Methods: To overcome these obstacles, we sacrificed the precision from mechanistic PK models with complex excretion equations to expediency of compartmental model in which a constant k_e is used to cover all the internal parameters. And the total cumulative amounts of urinary drug excretion $(X_{u}^{\infty})$ were estimated and introduced to the excretion equation so that urine data were likely to be fitted using a semi-log-terminal linear regression method. In addition, urinary excretion clearance (CL_r) could be calculated by single point plasma data to anchor the plasma concentration-time (C-t) curve based on the assumption that CL_r was kept constant throughout the PK process.

Results: After sensitivity analysis of two subjective judgements (the selection of the compartmental model and the selection of plasma time point to calculate CL_r), the performance of the optimized models was assessed using desloratadine or busulfan as model drugs in a variety of PK scenarios, from i.v. bolus/infusion to p.o. administration, from a single dose to multiple doses, and from rats to children. The fitting plasma drug concentrations of the optimal model were close to the observed value. Meanwhile, the drawbacks inherent to the simplified and idealized modeling strategy were fully identified.

Conclusions: The method proposed by this tentative proof-of-principle study was able to deliver acceptable plasma exposure curves and shed light on the future refinements.

Keywords: Pediatric; modeling; pharmacokinetics.