Population pharmacokinetics and Monte Carlo-based dosing optimization of trimethoprim-sulfamethoxazole

This study aimed to develop population pharmacokinetic (PopPK) models for intravenous sulfamethoxazole (SMX) and trimethoprim (TMP) to optimize dosing regimens for the treatment of Pneumocystis jirovecii pneumonia using these models. A prospective study was conducted in 79 patients treated with intravenous trimethoprim-sulfamethoxazole. PopPK models were developed using nonlinear mixed-effect modeling to evaluate the effects of liver function, kidney function, and genetic polymorphisms (NAT2 and CYP2C9) on pharmacokinetic parameters. Monte Carlo simulations were employed to identify the optimal dosing regimen. Pharmacokinetic analysis of SMX and TMP included 232 post-dose plasma concentrations from 79 adult patients. A one-compartment model with first-order elimination best described the data. Creatinine clearance (CrCL) was significantly correlated with the pharmacokinetic parameters of both SMX and TMP, while continuous renal replacement therapy significantly influenced only the SMX model. Liver function, NAT2, and CYP2C9 genotypes did not exhibit statistically significant effects on the models. Co-trimoxazole 50 mg/kg/day in a three-times-daily divided dose regimen is feasible for patients with CrCL of <15 mL/min. However, in patients with normal renal function, the guideline-recommended 90 mg/kg/day dose demonstrates a risk of supratherapeutic exposure. This study provides critical pharmacokinetic insights into SMX and TMP for patients, highlighting the necessity for dose adjustments in those with renal dysfunction. The currently recommended dosing regimens in clinical guidelines pose a risk of excessive drug exposure. Our study offers a more precise dosing strategy to optimize treatment efficacy and safety.