Background: ASN100 is a combination of two co-administered fully human monoclonal antibodies (mAbs), ASN-1 and ASN-2, that together neutralize the six cytotoxins critical to S. aureus pneumonia pathogenesis. ASN100 is in development for prevention of S. aureus pneumonia in mechanically ventilated patients. A population PK model was developed to characterize the time-course of ASN-1 and ASN-2 in ELF following intravenous administration of ASN100 in healthy subjects.
Methods: A total of 42 healthy subjects received a single dose of ASN-1 or ASN-2 alone (200 to 4000 mg) or ASN100 (3600 or 8000 mg; 1:1 ratio of ASN-1:ASN-2). All subjects contributed 13-17 serum samples for ASN‑1/ASN-2 assay. Twelve subjects contributed 2 bronchoalveolar lavage (BALF) samples each for ELF concentration assay (days 1 or 2 and days 8 or 30 after dosing). A previously-reported, linear, two-compartment population PK model for serum [ID Week 2017, Poster #1849] was expanded and fit to the ELF concentration-time data. Sequential analysis was used to fix serum PK as the driver for ELF PK; only those parameters controlling transfer into and out of the ELF were fit.
Results: An effect-site model adequately described the time-course of ELF concentrations. To allow for estimation of interindividual variability in the elimination from ELF, residual variability in ELF was fixed to that previously estimated for the serum PK data. Separate rate constants for transfer from serum to ELF were estimated for the 3600 and 8000 mg ASN100 dose groups to reflect the less than dose-proportional increase in ELF concentrations for both ASN-1 and ASN-2. Goodness-of-fit plots did not reveal any appreciable biases. A visual predictive check indicated that the model could adequately capture the observed data (Figure 1). Predicted ELF penetration using the ratio of ELF:serum AUC0-∞ was 33.0% for ASN-1 and 20.3% for ASN-2 following the selected clinical dose of 3600 mg.
Conclusion: A population PK model adequately described the time-course of ASN-1 and ASN-2 in ELF. ELF penetration was 20-33% following administration of the ASN100 clinical dose. These results should be interpreted with caution given the limited sample size (6 subjects per dose group) and limitations of urea-based normalization of BALF to ELF volume.
S. A. Van Wart,
Z. Magyarics, Arsanis Biosciences GmbH: Employee and Shareholder , Salary and stock options .
S. A. Luperchio, Arsanis, Inc.: Employee and Shareholder , Salary and stock options .
C. M. Rubino, Arsanis, Inc.: Research Contractor , Research support .
P. G. Ambrose, Arsanis, Inc.: Research Contractor , Research support .