Pharmacokinetic/Pharmacodynamic Evaluation of Solithromycin against Streptococcus pneumoniae Using Data from a Neutropenic Murine Lung Infection Model

Abstract

Solithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with communityacquired bacterial pneumonia. Using a neutropenic murine lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/ PD) index most closely associated with efficacy and the magnitude of such indices associated with solithromycin efficacy against Streptococcus pneumoniae. Plasma and epithelial lining fluid (ELF) samples for pharmacokinetics (PK) were collected serially over 24 hours from healthy mice administered single doses of solithromycin (0.625 to 40 mg/kg). Neutropenic CD-1 mice infected with 10 8 CFUs of one of five S. pneumoniae isolates were administered solithromycin (0.156 to 160 mg/kg/day) via oral gavage. Doses were administered in a fractionated manner for mice infected with one isolate, while mice infected with the remaining four isolates received solithromycin as either a regimen every 6 hours or every 12 hours. A three-compartment model best described solithromycin PK in the plasma and ELF (r 2 ϭ 0.935 and 0.831, respectively). The ratio of total-drug ELF to free-drug plasma area under the concentration-time curve (AUC) from time 0 to 24 hours was 2.7. Free-drug plasma and total-drug ELF AUC to minimum inhibitory concentration ratios (AUC/MIC ratios) were most predictive of efficacy (r 2 ϭ 0.851 and 0.850, respectively). The magnitude of free-drug plasma/total-drug ELF AUC/MIC ratios associated with net bacterial stasis and a 1-and 2-log 10 CFU reduction from baseline was 1.65/1.26, 6.31/15.1, and 12.8/59.8, respectively. These data provided dose selection support for solithromycin for clinical trials in patients with community-acquired bacterial pneumonia.

Penetration of Antibacterial Agents into Pulmonary Epithelial Lining Fluid: An Update

“…Compared with the other macrolides and ketolides, the AUC values of nafithromycin in both plasma and ELF were substantially higher. Specifically, the mean nafithromycin AUC 24 is about three times greater than observed with solithromycin, which could be advantageous for nafithromycin in the treatment of bacterial pneumonia, although the MIC 90 is higher for solithromycin [65,67]. The pattern of intrapulmonary penetration of the AUC values of ELF and AM being circa 10-fold and 100fold higher, respectively, than total plasma concentrations for these two novel agents are consistent with previously reported findings for azithromycin, clarithromycin, and telithromycin.…”

“…The modeling supported a high AUC/MIC target attainment following administration of the oral dosing regimen of solithromycin 800 mg on day 1 and 400 mg once daily on days 2-5. Okusanya and colleagues performed a PK/PD analysis of solithromycin in a neutropenic murine lung infection model [65]. The observed solithromycin total drug ELF to unbound drug plasma AUC 24 ratio in mice was 2.7, which was considerably lower than solithromycin penetration in human lung ELF.…”

Development of an Adult Physiologically Based Pharmacokinetic Model of Solithromycin in Plasma and Epithelial Lining Fluid

“…High target attainments for simulated ELF concentrations suggests that the oral dosing regimen evaluated in clinical trials (800 mg on day 1, followed by 400 mg on days 2–5) is appropriate for the treatment of CABP. Similar findings were observed for a previously developed population‐based PK model: net bacterial stasis and a 1‐log 10 colony forming unit reduction of ≥99.9% and 90.9%, respectively, for MIC values between 0.125 and 1 µg/mL . Although PBPK and population‐based PK modeling approaches are different, similar PK/PD relationships observed between the two models increases the confidence of our results.…”

New Oxazolidinones for Tuberculosis: Are Novel Treatments on the Horizon?

“…These studies suggested that sutezolid had superior activity to linezolid [ 18 , 19 ]. A comparison of the activity of sutezolid and its metabolite U-101603 demonstrated that the latter had greater activity against nonreplicating persisters than its parent compound, which was more active in the log growth phase [ 20 ]. The addition of rifampicin was synergistic with sutezolid and was needed to prevent resistance associated with sutezolid monotherapy [ 21 ].…”