Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children [PublishAheadOfPrint]

Trimethoprim/sulfamethoxazole (TMP/SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii in children. Pharmacokinetic (PK) data in infants and children are limited and optimal dosing is not known. We performed a multicenter, prospective PK study of TMP/SMX in infants and children. Separate population PK models were developed for enteral TMP and SMX using nonlinear mixed effects modeling. Optimal dosing was determined based on matching adult TMP exposure and attaining the surrogate pharmacodynamic (PD) target for efficacy---a free TMP concentration above the minimal inhibitory concentration (MIC) at 50% of the dosing interval. A total of 153 subjects (240 PK samples) with a median (range) postnatal age of 8 years (0.1–20) contributed to the analysis for both drugs. A 1-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to serum creatinine and albumin, respectively. Oral TMP/SMX 8/40 mg/kg/day divided every 12h matched adult exposure after TMP/SMX 320/1600 mg/day divided every 12h and achieved the PD target for an MIC of 0.5 mg/L in >90% of infants and children. Oral TMP/SMX 12/60 and 15/75 mg/kg/day divided every 12h matched adult exposure after TMP/SMX 640/3200 mg/day divided every 12h in subjects 6–<21 years and 0–<6 years of age, respectively, and was optimal for bacteria with an MIC up to 1 mg/L.

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