1849. Population Pharmacokinetic Model for Intravenous ASN100 in Healthy Subjects
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD

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 beta-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.

Scott A. Van Wart, Ph.D., M.S.1, Christopher Stevens, M.D.2, Zoltan Magyarics, M.D., Ph.D.3, Steven A. Luperchio, Ph.D., CMPP2 and Paul G. Ambrose, Pharm.D., FIDSA1, (1)ICPD, Schenectady, NY, (2)Arsanis, Inc., Waltham, MA, (3)Arsanis Biosciences GmbH, Vienna, Austria

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

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