Population Pharmacokinetic Model for Intravenous ASN100 in Healthy Subjects

• Published in: Open forum infectious diseases Vol. 4; no. suppl_1; p. S529
• Main Authors: Van Wart, Scott A, Stevens, Christopher, Magyarics, Zoltan, Luperchio, Steven A, Ambrose, Paul G
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.10.2017
• ISSN: 2328-8957; 2328-8957
• DOI: 10.1093/ofid/ofx163.1379

Abstract Background ASN100 is a combination of ASN-1 and ASN-2, two human monoclonal antibodies (mAbs) which selectively bind to 6 S. aureus cytotoxins. ASN100 is in development for prevention of pneumonia in mechanically ventilated patients. A population pharmacokinetic (PK) model was developed for both ASN-1 and ASN-2 following monotherapy or simultaneous administration (ASN100) using dose-escalation data from a first-in-human study. Methods A total of 42 healthy subjects received a single 1 hour intravenous (IV) infusion of either ASN-1 or ASN-2 alone (200 to 4000 mg) or ASN100 (3600 or 8000 mg; 1:1 ratio of ASN-1 and ASN-2). Serial PK samples were collected for up to 100 days post-dose and concentrations of ASN-1 and ASN-2 were determined in serum using an enzyme-linked immunosorbent assay (ELISA). Separate linear two-compartment models with zero-order input and first-order elimination were fit to the serum PK data for ASN-1 and ASN-2. Results A linear two-compartment model best described the PK data for ASN-1 and ASN-2. There was no evidence of deviation from linear or dose-proportional PK over the dose range studied, differences between monotherapy and combination therapy, or presence of anti-drug antibody formation based upon visual inspection of individual PK profiles. There was excellent agreement between the observed and population mean (r2 = 0.79 and 0.93) and individual post-hoc predictions (r2 = 0.88 and 0.98) for ASN-1 and ASN-2, respectively. The population mean clearance (CL) was 0.267 and 0.212 L/day, central volume (Vc) was 3.84 and 4.17 L, distribution CL was 0.586 and 1.23 L/day, and peripheral volume was 3.48 and 3.78 L for ASN-1 and ASN-2, respectively. For parsimony, inter-individual variability was forced to be the same for ASN-1 and ASN-2 and was 22.7% CV for CL, 21.2% CV for Vc, and 34.4% CV for Vp. The mean alpha- and β-phase elimination half-lives for ASN-1 were 1.91 and 21.6 days and for ASN-2 were 1.08 and 27.5 days, respectively, as calculated using the individual post-hoc parameters. Conclusion ASN100 was safe and well tolerated. The PK of both ASN-1 and ASN-2 were linear and dose-proportional over a wide dose range. Although there were slight PK differences between ASN-1 and ASN-2, the PK of both were within the range expected for IgG1 mAbs. Disclosures S. A. Van Wart, Arsanis: Research Contractor, Research support; C. Stevens, Arsanis Inc.: Employee and Shareholder, Salary; Z. Magyarics, Arsanis Biosciences GmbH: Employee and Shareholder, Salary; S. A. Luperchio, Arsanis Inc: Employee and Shareholder, Salary; P. G. Ambrose, Arsanis: Research Contractor, Research support