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

Abstract

Solithromycin is a fluoroketolide antibiotic under investigation for community‐acquired bacterial pneumonia (CABP). We developed a whole‐body physiologically based pharmacokinetic (PBPK) model for solithromycin in adults using PK‐Sim and MoBi version 6.2, which incorporated time‐dependent CYP3A4 auto‐inhibition. The model was developed and evaluated using plasma and epithelial lining fluid (ELF) concentration data from 100 healthy subjects and 22 patients with CABP (1,966 plasma, 30 ELF samples). We performed population simulations and calculated the number of observations falling outside the 90% prediction interval. For the oral regimen (800 mg on day 1 and 400 mg daily on days 2–5) that was evaluated in phase III studies, 11% and 23% of observations from healthy adults fell outside the 90% prediction interval for plasma and ELF, respectively. This regimen should be effective because ≥97% of simulated adults achieved area under the concentration vs. time curve (AUC) to minimum inhibitory concentration ratios associated with a log10 colony forming unit reduction in ELF.

Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge

“…Many have lower concentrations in the lung compared with plasma; however, there are several that accumulate in the lung. For example, following oral administration of solithromycin, a lipophilic drug with good permeability, ureacorrected BAL concentrations are 2-28fold higher than plasma concentrations [Rodvold, 2012;Salerno, 2017].…”

Pitfalls of using numerical predictive checks for population physiologically-based pharmacokinetic model evaluation

“…Use of a clear criterion for model acceptance/rejection has yet to be established. Additionally, computed NPC are typically not assessed for statistical significance (5,6). As a result, models are deemed successful even when the proportions of data falling outside the model's 90% PI exceed the nominal value (10%).…”

“…In contrast, NPC quantitatively compare the proportion of observed data that corresponds to modelsimulated percentiles with their expected proportion. The proportion of observed data falling outside the model's 90% prediction interval (PI) represents a commonly used NPC for assessing model quality (5,6). For suitable models, the proportion of observed data exceeding model-based percentiles should be congruent to the expected proportion (e.g., 10% of observations are expected to exceed the model's 90% PI).…”

Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

“…(1,966 plasma samples) (Supplemental Table 1) (Salerno et al, 2017). A mean virtual individual was used for model development based on demographics of the clinical study in healthy adults: a 44.7-year-old black American man with a weight of 85.6 kg and a height of 180.9 cm.…”

“…Using pooled human liver microsomes with midazolam as the CYP3A substrate, solithromycin was reported to be a potent CYP3A time-dependent inhibitor with an inactivation rate constant (k inact ) and a concentration of half-maximal inactivation (K I ) of 0.022 min -1 and 0.038 µg/mL, respectively (Salerno et al, 2017). However, recombinant studies with CYP3A4, CYP3A5, and CYP3A7 were not performed.…”