Population pharmacokinetic modeling of sulfamethoxazole, sulfadiazine and sulfadimethoxine combined with trimethoprim in calves

Sulfonamides (S) are long-established antibacterial drugs frequently combined with trimethoprim (TMP) for synergistic effects against bacterial infections in food-producing animals, such as bovine respiratory diseases. In veterinary medicine, the current administered TMP:S ratio of 1:5 is based on the human dosing regimen that is limited to the single combination of TMP and sulfamethoxazole (SMX), targeting an in vivo concentration ratio of 1:19, considered an appropriate synergistic ratio against human pathogens. However, several sulfonamides are used in veterinary practice each leading to distinct pharmacokinetic profiles and thereby questioning the relevance of extrapolating this dose ratio. This study characterized the parenteral pharmacokinetics (PK) of three TMP/S combinations in calves. Data were used to develop population PK models and to simulate in vivo free-concentration ratios at the herd level. A 2-compartment model fitted best sulfadiazine (SDZ), SMX and TMP data while sulfadimethoxine (SDMX) needed a third compartment. SDMX had the lowest clearance (0.02 L/h/kg) while SMX and SDZ showed similar values (0.13 and 0.12 L/h/kg, respectively). TMP exhibited the highest clearance (1.41 L/h/kg). Elimination half-lives were 19.67 h for SDMX, 3.54 h for SDZ, 2.21 h for SMX and 1.39 h for TMP. Monte Carlo simulations indicated that only 0.2% (TMP/SDZ), 11.6% (TMP/SMX) and 21% (TMP/SDMX) of simulated calves (n = 50,000) reached ratios between 1:10 - 1:50 at marketed doses. These results provide a first step toward optimizing the antimicrobial activity of these antibacterial, highlighting the need for further PD and PK/PD investigations.