Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

Abstract

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the 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 TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-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 of distribution (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.

Keywords: children; infants; methicillin-resistant Staphylococcus aureus; pharmacokinetics; sulfamethoxazole; trimethoprim.

FIG 1

Trimethoprim (TMP) (A) and sulfamethoxazole (SMX) (B) concentrations versus time after the last dose.

FIG 2

TMP diagnostic plots for the final model. (A) Observed versus population predictions; (B) observed versus individual predictions; (C) conditional weighted residuals versus time; (D) conditional weighted residuals versus population predictions. The dashed lines represent the loess curve. The solid grey lines represent conditional weighted residual values of 0 and ±2. Concentrations below the lower limit of quantifications (LLOQ) were imputed as LLOQ/2.

FIG 3

SMX diagnostic plots for the final model. (A) Observed versus population predictions; (B) observed versus individual predictions; (C) conditional weighted residuals versus time; (D) conditional weighted residuals versus population predictions. The dashed lines represent the loess curve. The solid grey lines represent conditional weighted residual values of 0 and ±2. Concentrations below the lower limit of quantifications (LLOQ) were imputed as LLOQ/2.

FIG 4

Target attainment rates by MIC for free trimethoprim concentrations at 50% of the dosing interval in 1,000 simulated children by age group. The solid horizontal black lines represent the 90% target attainment rate. div, the dose was divided by administration by the indicated times.

FIG 5

Target attainment rate for Pneumocystis jirovecii by age group. The solid horizontal black line represents the 90% target attainment rate. The target was defined as a total maximum concentration at steady state (C_max,ss) of ≥3 mg/liter.