Population PK modeling of different sulfonamides in association with trimethoprim in pigs - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Proceedings Journal of Veterinary Pharmacology and Therapeutics Year : 2023

Population PK modeling of different sulfonamides in association with trimethoprim in pigs

Abstract

Introduction: Due to the restrictive use of critical antibiotics by veterinarians in Europe, the use of first-line antibiotics such as the combination of sulfonamides (S) and trimethoprim (TMP) is likely to increase, especially in pig production. The ratio of TMP:S doses in nearly all marketed veterinary formulations is 1:5, which is supposed to produce an in vivo synergistic ratio of plasma concentrations of 1:19. However, sulfonamides drugs are quite different and lead to major differences in PK profiles, challenging the occurrence of this constant ratio of 1:19 for TMP:S in plasma. Objectives: This study aims to develop a modern population PK model for sulfadiazine (SDZ) and sulfadimethoxine (SDMX) in association with TMP to compare the evolution of the TMP:S ratios between these 2 sulfonamides over time. Materials and Methods: 16 pigs were used (8 pigs for SDZ/TMP and 8 pigs for SDMX/TMP). Each association was given by IV, oral (gavage) and IM route (only for SDZ) in a cross-over design at the recommended dosing (one dose per route of administration). A rich blood sampling was carried-out and plasma samples were assayed thanks to a sensitive HPLC method. A non-linear mixed effect modeling approach was used to estimate PK parameters (typical values and inter-individual variabilities) for each drug and compute the evolution of the TMP:S ratios over time via MonteCarlo simulations (Monolix Suite v2021R2). Results: A bi-compartmental model best described the PK data for each of the 3 drugs. SDZ and SDMX have significant different half-lives (median values of 4.1 h and 13.5 h, respectively) in pigs. The half-life for TMP was of the same order as for SDZ (median value of 2.3 h). Based on the population PK parameters, simulations (n = 500 pigs) were performed with the conventional dosing regimen (25:5 mg/kg of Sulfonamides:TMP over 5 days by oral route). The average ratio over 140 h of free TMP:S concentrations stayed between 1:10 and 1:100 for 92% and 82% of pigs, regarding SDZ and SDMX respectively. Concerning the duration of the TMP:S ratio being between 1:10 and 1:100 (over 140 h), the median time was 65 h (i.e. 46%) and 38 h (i.e. 27%) for SDZ and SDMX respectively, with a high inter-individual variability. Conclusion: The in vivo ratio of TMP:S varies greatly over time between sulfonamide drug and between individual, questioning the current formulations and dosing regimens, especially for SDMX/TMPFurther work with a third sulfamide (sulfamethoxazole) is ongoing.

Dates and versions

hal-04352560 , version 1 (19-12-2023)

Identifiers

Cite

Alexis Viel, Marine Boulanger, Jean-François Taillandier, Michel Laurentie, Jérôme Henri, et al.. Population PK modeling of different sulfonamides in association with trimethoprim in pigs. 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology, Journal of Veterinary Pharmacology and Therapeutics, 46 (S1), pp.82-83, 2023, ⟨10.1111/jvp.13277⟩. ⟨hal-04352560⟩
12 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More