Constant-Speed Intravenous Infusion Model Determines Pharmacokinetic Parameters: Phylloquinone as an Example

Reported pharmacokinetic parameters, particularly half-life (t1/2), show substantial variability for phylloquinone, due to the limitations of classical pharmacokinetic models. The study aims to determine the pharmacokinetic parameters of phylloquinone using a Constant-Speed Intravenous Infusion (CSII) strategy, designed to overcome the limitations of the low terminal-phase concentration quality following Intravenous (IV) bolus administration.

The Sprague-Dawley rats received a constant-rate infusion of phylloquinone for 15 hours. Plasma concentrations were quantified by a validated HPLC method, and pharmacokinetic parameters following CSII were derived by fitting the data to a one-phase exponential association model.

Following CSII, phylloquinone exhibited a t1/2 of 4.27 ± 0.47 h, CL of 56.93 ± 9.00 mL/h, and Vd of 321.86 ± 29.25 mL without the limitation of low terminal-phase concentrations. Following IV, the t1/2 and Vd of phylloquinone based on two-compartment analysis were larger than those based on one-compartment analysis. Noncompartmental analysis revealed significant differences in t1/2 and Mean Residence Time (MRT) across varying sampling durations. Meanwhile, the t1/2 of phylloquinone was markedly different from its MRTequated half-life. Additionally, the Vd estimated after CSII was larger than that obtained from the IV bolus.

The CSII strategy avoids reliance on error-prone terminal-phase data by deriving the pharmacokinetic parameters from the ascending phase of the concentration-time profile. This approach provided robust parameter estimates and helped clarify inconsistencies observed with traditional IV bolus analyses.

CSII provides a valuable complementary strategy for pharmacokinetic parameter estimation, especially for compounds with problematic terminal-phase analysis or those routinely given by CSII. Its broader applicability warrants further investigation.