Population pharmacokinetic modeling of sulfadimethoxine, sulfadiazine and sulfamethoxazole combined to trimethoprim in pigs

Sulfonamides (S) are old antibiotics combined with trimethoprim (TMP) for synergistic effects against pathogens responsible for a variety of infections in food-producing animals. In growing pigs, the TMP:S ratio is 1:5 based on human TMP/sulfamethoxazole (SMX) dosing which aims to obtain an in vivo ratio concentration of 1:19 considered as optimal against human pathogens. However, different sulfonamides with different pharmacokinetic profiles are used in pigs limiting this direct extrapolation from human. The aim was to conduct a PK study in pigs for three commonly used TMP/S combinations and to analyze data using population pharmacokinetic modeling. We found that a 2-compartment structural model fitted best the four drug PK data. TMP has the highest clearance values (0.48 L/h/kg) compared to SMX (0.21 L/h/kg), SDZ (0.12 L/h/kg) and SDMX (0.015 L/h/kg). SDMX has the longest plasma elimination half-life (14.8 h), followed by SDZ (3.7 h), TMP (2.9 h) and SMX (2.2 h). Monte Carlo simulations (n = 50,000 pigs) showed that only for 8.8%, 46.8%, and 76.5% of pigs for TMP/SMX, TMP/SDZ and TMP/SDMX, respectively, the free plasma concentration ratio fell within the range of 1:10-1:50 at the marketed doses administered. These results should be further linked to pharmacodynamics to optimize the use of these important antimicrobials drugs in veterinary medicine.