Population Pharmacokinetics and Safety of Solithromycin following Intravenous and Oral Administration in Infants, Children, and Adolescents

Abstract

Solithromycin is a novel fluoroketolide antibiotic which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age, 6 years [age range, 4 days to 17 years]) were administered intravenous (i.v.) or oral (capsules or suspension) solithromycin (i.v., 6 to 8 mg/kg of body weight; capsules/suspension, 14 to 16 mg/kg on days 1 and 7 to 15 mg/kg on days 2 to 5). PK samples were collected after the first and multidose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (n = 13; median age, 16 years [age range, 12 to 17 years]) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and postmenstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg i.v. daily and oral dosing of 20 mg/kg on day 1 (800-mg adult maximum) followed by 10 mg/kg on days 2 to 5 (400-mg adult maximum) would achieve a pediatric solithromycin exposure consistent with the exposures observed in adults. Seventy-six treatment-emergent adverse events (TEAEs) were reported in 40 subjects. Diarrhea (6 subjects) and infusion site pain or phlebitis (3 subjects) were the most frequently reported adverse events related to treatment. Two subjects experienced TEAEs of increased hepatic enzymes that were deemed not to be related to the study treatment. (The phase 1 pediatric studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01966055 and NCT02268279.).

Keywords: antibiotics; pediatrics; pharmacokinetics; safety; solithromycin.

FIG 1

Solithromycin concentration versus time after the last dose on a semilog scale.

FIG 2

Observations versus population and individual predictions for the final solithromycin population pharmacokinetic model. The dashed gray line denotes the line of unity.

FIG 3

Standardized visual predictive check (SVPC) plot of solithromycin observation percentiles versus time after the last dose for the final population pharmacokinetic model. The dashed blue lines represent the 5th and 95th percentiles of the model-predicted P_ij, where P_ij is the percentile of the jth observation for the ith subject. The red dashed line is the 50th percentile of the model-predicted P_ij. The black line corresponds to a P_ij of 0.5. Open circles are the calculated P_ij for each observation. The percentage of observed concentrations that were outside the 90% prediction interval was 8.2%.

FIG 4

Box plots of the simulated day 5 area under the concentration-versus-time curve from 0 to 24 h (AUC_0–24) across age groups using 8 mg/kg i.v. daily (A) (400 mg maximum) and 20 mg/kg on day 1 (800 mg maximum) followed by 10 mg/kg on days 2 to 5 (400 mg maximum) for the suspension (B) and capsules (C). Capsule doses were rounded upwards to the nearest 200 mg. The dashed line and gray region denote the geometric mean and range of the adult exposures in the phase 3 studies, respectively. Because phase 3 adult studies evaluated daily oral dosing and an i.v.-to-oral formulation switch, the same geometric mean and range (estimates following multiple oral dosing) are visualized across all 3 panels. The dashed lines used in all panels represent the geometric mean day 4 exposure following capsule daily dosing in the phase 3 study. The lower and upper hinges of the box plot correspond to the 25th and 75th percentiles, respectively. The upper and lower whiskers extend to the largest and smallest value no further than 1.5 · interquartile range (IQR), respectively. Closed circles represent outlier values outside 1.5 · IQR. Simulated extreme outlier values of >150 μg · h/ml (1.2% and <0.5% of the simulated data points for the i.v. and oral [suspension/capsule] formulations, respectively) are not plotted for ease of visualization.