# Pharmacokinetics of Lekethromycin in Swine Following Intramuscular Administration at Different Doses with a Single Intravenous Reference Dose for Absolute Bioavailability and Matrix Comparison

## TL;DR

This study examines how lekethromycin behaves in pigs after different doses, finding that plasma is more reliable than whole blood for measuring drug levels.

## Contribution

The study reveals that plasma is more suitable than whole blood for evaluating lekethromycin's bioavailability due to saturable blood cell partitioning.

## Key findings

- Lekethromycin shows non-linear pharmacokinetics in whole blood but linear in plasma.
- Plasma concentrations are more reliable for assessing bioavailability due to saturable cell uptake.
- Absolute bioavailability of lekethromycin in plasma ranges from 83.2% to 119.5%.

## Abstract

This study investigated the pharmacokinetics of lekethromycin in pigs after intramuscular administration at 1–10 mg/kg, with a single intravenous reference dose (5 mg/kg) included solely to estimate absolute bioavailability (F) and to support matrix comparison between whole blood and plasma. Forty-two healthy pigs were enrolled and housed under standardized conditions for the duration of the study. Each pig received a single administration of lekethromycin according to their assigned dosing route. Serial blood sampling was performed at scheduled time points, and concentrations in whole blood and plasma were quantified by UPLC–MS/MS. Pharmacokinetic parameters were derived with dedicated WinNolin software (version 8.3.4 Certara; Pharsight, Mountain View, CA, USA), and dose proportionality was assessed using a linear mixed-effects approach. Whole-blood exposure (1–10 mg/kg) was non-dose-proportional, consistent with saturable blood cell partitioning, whereas linear pharmacokinetics were observed in plasma. Furthermore, the study highlighted that plasma is the optimal matrix for accurately evaluating absolute bioavailability, providing a robust scientific foundation for determining the clinical dosing regimen of lekethromycin.

Lekethromycin (LKMS) is a novel macrolide veterinary antimicrobial. Its propensity for intracellular accumulation causes discrepancies between whole blood and plasma concentrations, complicating pharmacokinetic evaluations. This study compared the pharmacokinetic characteristics, dose proportionality, and bioavailability of LKMS in whole blood and plasma following intramuscular administration in pigs. Forty-two healthy pigs received LKMS via a single intravenous reference dose (5 mg/kg) for absolute bioavailability estimation or intramuscular (1, 2.5, 5, and 10 mg/kg) injection. Pharmacokinetic parameters were calculated using non-compartmental analysis, and dose proportionality was evaluated via a power model. LKMS exhibited rapid absorption and slow elimination, with a plasma half-life of 49.25 to 67.63 h. Whole blood exposure and peak concentrations were 1.5 to 3 times higher than in plasma, indicating extensive blood cell partitioning. As the intramuscular dose increased, the whole blood-to-plasma concentration ratio decreased from 2.83 to 1.15, suggesting a saturable cell uptake mechanism. Consequently, LKMS exhibited non-linear pharmacokinetics in whole blood but demonstrated linear, dose-proportional pharmacokinetics in plasma. Absolute bioavailability based on plasma ranged from 83.2% to 119.5%. Due to saturable blood cell binding, plasma is the optimal matrix for accurately evaluating LKMS systemic exposure and bioavailability in swine.