External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole

Abstract

The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study) (J. Autmizguine, C. Melloni, C. P. Hornik, S. Dallefeld, et al., Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more-traditional PK sample collection and independently developed new popPK models of TMP-SMX using this external data set. The POPS data set and the external data set were each used to evaluate both popPK models. The external TMP model had a model and error structure identical to those of the POPS TMP model, with typical values for PK parameters within 20%. The external SMX model did not identify the covariates in the POPS SMX model as significant. The external popPK models predicted higher exposures to TMP (median overprediction of 0.13 mg/liter for the POPS data set and 0.061 mg/liter for the external data set) and SMX (median overprediction of 1.7 mg/liter and 0.90 mg/liter) than the POPS TMP (median underprediction of 0.016 mg/liter and 0.39 mg/liter) and SMX (median underprediction of 1.2 mg/liter and 14 mg/liter) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for resistant pathogens with a MIC of 1 mg/liter, although the required dose increase based on the external model was lower. (The POPS and external studies have been registered at ClinicalTrials.gov under registration no. NCT01431326 and NCT02475876, respectively.).

Keywords: and sulfamethoxazole; pediatric; population pharmacokinetics; sulfamethoxazole; trimethoprim.

FIG 1

Goodness-of-fit plots comparing TMP PREDs with observations. PREDs were obtained by fixing the parameters in the published POPS model or the external model developed from the current study. The dashed line represents the line of unity; the solid line represents the best-fit line. We excluded 22 (9.3%) TMP samples and 15 (6.4%) SMX samples from the POPS data that were BLQ.

FIG 2

Goodness-of-fit plots comparing SMX PREDs with observations. PREDs were obtained by fixing the model parameters for the published POPS model or the external model developed from the current study. The dashed line represents the line of unity; the solid line represents the best-fit line. We excluded 22 (9.3%) TMP samples and 15 (6.4%) SMX samples from the POPS data that were BLQ.

FIG 3

pcVPCs for each TMP model–data set combination. The red shaded region represents the simulated 95% prediction interval for the median; the solid red line represents the observed median; the blue region represents the simulated 95% prediction interval for the 2.5th and 97.5th percentiles; the dashed blue lines represent the observed 2.5th and 97.5th percentiles; and the horizontal dashed black line represents the lower limit of quantification.

FIG 4

pcVPCs for each SMX model–data set combination. The red shaded region represents the simulated 95% prediction interval for the median; the solid red line represents the observed median; the blue region represents the simulated 95% prediction interval for the 2.5th and 97.5th percentiles; the dashed blue lines represent the observed 2.5th and 97.5th percentiles; and the horizontal dashed black line represents the lower limit of quantification.

FIG 5

Box plots of the AUC_ss (area under the plasma concentration-versus-time curve in one dosing interval at steady state) for TMP in virtual children (2 months to <2 years, 2 to <6 years, 6 to <12 years, and 12 to <18 years of age) compared to the exposure of adults taking 160 mg every 12 h. The mean ± twice the standard deviation for AUC_ss in one 12-h dosing interval at steady state based on seven studies of adults aged 18 to 60 years without significant renal or hepatic impairment taking 160 mg of TMP every 12 h (Q12h) is plotted in yellow (8–10, 12–15).