Physiologically Based Pharmacokinetic Modeling of Meropenem in Preterm and Term Infants

Abstract

Background: Meropenem is a broad-spectrum carbapenem antibiotic approved by the US Food and Drug Administration for use in pediatric patients, including treating complicated intra-abdominal infections in infants < 3 months of age. The impact of maturation in glomerular filtration rate and tubular secretion by renal transporters on meropenem pharmacokinetics, and the effect on meropenem dosing, remains unknown. We applied physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of meropenem in preterm and term infants.

Methods: An adult meropenem PBPK model was developed in PK-Sim^® (Version 8) and scaled to infants accounting for renal transporter ontogeny and glomerular filtration rate maturation. The PBPK model was evaluated using 645 plasma concentrations from 181 infants (gestational age 23-40 weeks; postnatal age 1-95 days). The PBPK model-based simulations were performed to evaluate meropenem dosing in the product label for infants < 3 months of age treated for complicated intra-abdominal infections.

Results: Our model predicted plasma concentrations in infants in agreement with the observed data (average fold error of 0.90). The PBPK model-predicted clearance in a virtual infant population was successfully able to capture the post hoc estimated clearance of meropenem in this population, estimated by a previously published model. For 90% of virtual infants, a 4-mg/L target plasma concentration was achieved for > 50% of the dosing interval following product label-recommended dosing.

Conclusions: Our PBPK model supports the meropenem dosing regimens recommended in the product label for infants <3 months of age.

Fig. 1

Simulation of meropenem concentration vs. time for one hundred virtual adults. The adult meropenem PBPK model was developed and evaluated using published plasma meropenem concentration vs. time data digitized for a 0.5 and 1 g intravenous (IV) infusion administered over 30 minutes. In a) and b), digitized observed mean plasma concentration vs. time data (black circles with ± standard deviation as black lines) [8] were compared with the 90% prediction interval of the simulated meropenem plasma concentration vs. time profile (red shaded region). In c) and d), digitized observed plasma concentration vs. time data (black circles) [6,7,25,26] were compared with the median and 90% prediction interval of the simulated meropenem plasma concentration vs. time profile (red shaded region).

Fig 2.

Pediatric PBPK model evaluation. The adult PBPK model was scaled to infants and evaluated using digitized published data for preterm and term infants [13]. A virtual population (n=200) was generated based on published demographic information, simulations were performed using the PBPK model, and the results plotted as the 90% prediction interval (shaded region) overlaid with mean (± standard deviation [SD]) observed meropenem plasma concentration vs. time data after a single IV infusion (30 minutes duration). The colors and symbols represent different body weight-based dosing regimens. For the full-term infant simulations, the virtual infants’ gestational age and postnatal age were 37 to 42 weeks and one day, respectively. For the preterm infant simulations, the virtual infants’ gestational age and postnatal age was 29 to 36 weeks and one day, respectively.

Fig. 3

Observed vs PBPK model simulated dose-normalized meropenem concentration vs. time in infants. Dose-normalized and time-corrected observed plasma concentrations of meropenem (black circles) were compared with the 90% prediction interval (red shaded region) and the median (solid black line) simulated meropenem plasma concentration vs. time profile for a virtual neonatal population dosed 1 mg/kg of meropenem by intravenous (IV) infusion over 30 minutes. In a), 1000 virtual infants with gestational age (GA) < 32 weeks and postnatal age (PNA) < 14 days received meropenem every 12 hours. In b), 3000 virtual infants (1000 virtual infants per each of the following age groups: GA < 32 weeks and PNA ≥ 14 days; GA ≥ 32 weeks and PNA < 14 days; and GA ≥ 32 weeks and PNA ≥ 14 days) received meropenem every 8 hours. For the ease of visualization, x-axis is restricted up to 150 h, and the lower limit of y-axis is restricted up to 0.005 mg/L. These axes restrictions removed six concentrations from a) after 150 h time, and 29 concentrations from b) (19 of them were after 150 h and ten were below 0.005 mg/L/mg Dose).

Fig. 4

Comparison of body weight-normalized meropenem clearance in a virtual population of 4000 infants using the final physiologically based pharmacokinetic (PBPK) model (black open circles) and individual estimates of body weight-normalized clearance obtained from a previously published population pharmacokinetic (PopPK) analysis (red solid circles) [15] by postmenstrual age. The blue line indicates the smooth line based on a generalized additive model (default when sample size >1000) using the geom smooth function in the R package ggplot2. The virtual population for PBPK model simulations is comprised of 1000 virtual infants for each of the following age groups: gestational age (GA) < 32 weeks and postnatal age (PNA) < 14 days; GA < 32 weeks and PNA ≥ 14 days; GA ≥ 32 weeks and PNA < 14 days; and GA ≥ 32 weeks and PNA ≥ 14 days of age. The body weight and height range for each age group were selected to match the observed data’s demographic characteristics (Table S3).

Fig. 5

Target attainment analysis performed using the final physiologically based pharmacokinetic (PBPK) model to evaluate the product label recommended meropenem dosing for infants < 3 months of age with complicated intra-abdominal infections. One thousand virtual infants for each age cohort (stratified into four gestational age [GA] and postnatal age [PNA] groups) were dosed with the label recommended meropenem intravenous (IV) dosing. The percentage of the dosing interval for which the meropenem steady-state unbound plasma concentration was above the minimum inhibitory concentrations (MIC) of 0.25 to 16 mg/L was calculated for 90% of virtual infants (solid black line) and plotted against MIC on the x-axis. The horizontal dotted blue and red lines indicate the achievement of unbound plasma concentration higher than MICs for 50% and 75% of the dose interval, respectively. The two vertical lines indicate 2 mg/L (red) and 4 mg/L (blue) MICs. The intersection of the blue horizontal line and vertical lines indicates unbound plasma concentration achievement above 2 and 4 mg/L for 50% of the dosing interval.