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P008. Pharmacokinetics and pharmacodynamics in cynomolgus monkeys of AMG 181, a fully human anti α4 β7 antibody for treating inflammatory bowel disease

W.‑J. Pan1, S. Lear2, S. Patel1, P. Prince1, D. Doherty1, C.‑Y. Tam1, C. Sheckler1, H. Hsu3, W. Rees2, A. Anderson4, J. Wisler5, K. Reynhardt6, J. Lynch7, J. Brandvig8, L. Wienkers1, D. Borie9

1Amgen Inc., Pharmacokinetics and Drug Metabolism, Seattle, United States; 2Amgen Inc., Molecular Sciences and Computational Biology, Seattle, United States; 3Amgen Inc., Inflammation, Thousand Oaks, United States; 4Amgen Inc., Molecular Sciences and Computational Biology, Thousand Oaks, United States; 5Amgen Inc., Toxicology, Thousand Oaks, United States; 6Amgen Inc., Clinical Immunology, Seattle, United States; 7Charles River Laboratories, Preclinical Services, Reno, United States; 8Amgen Inc., Toxicology, Seattle, United States; 9Amgen Inc., Inflammation Clinical Research, Thousand Oaks, United States

Background: To determine the pharmacokinetics and pharma­codynamics (PK/PD) of AMG 181 after single or weekly IV or SC administration in cynomolgus monkeys.

Methods: In two PK/PD studies, 3–6 male monkeys/group received single doses of 0, 0.01, 0.1, 1, 3, 9 mg/kg IV or 0, 3 or 9 mg/kg SC. In the two-dose toxicology study, 4 monkeys/sex/group received two weekly doses of 0, 0.5, or 80 mg/kg SC. In the 3‑month GLP toxicology study, 6 monkeys/sex/group were dosed weekly for 13 weeks at 0, 5, 20, or 80 mg/kg SC or 80 mg/kg IV. Blood samples were collected for PK and antibodies in serum, while whole blood 4‑color flow cytometry was performed to assess α4β7 receptor occupancy (RO) and CD4 memory and naïve T cell counts at predefined timepoints. PK samples were assayed using a validated ECL method with an LLOQ of 2 ng/mL. PK data were analyzed with a noncompartmental method. Population PK/PD modeling was conducted on AMG 181 concentration and RO data.

Results: Single-dose Cmax was dose-proportional under 0.01–80 mg/kg IV, while AUC increased more than dose proportionally, indicating the presence of target-mediated disposition and the effect of immunogenicity. The estimated half-life was 18 days during the linear disposition phase. Volume of distribution (110 mL) showed AMG 181 distribution mainly in the central circulation. AMG 181 was extensively absorbed after SC administration with absolute bioavailability of 80%. Dose-proportional exposures were observed at 5–80 mg/kg SC after a single dose and at 20–80 mg/kg SC after 13 repeated doses. AMG 181 accumulated 2 to 3 fold after thirteen weekly 80 mg/kg SC or IV doses. An AMG181 EC50 value of 14 ng/mL was calculated from models correlating PK and α4β7 receptor saturation on both CD4+ central memory and naïve T cell subsets. The magnitude and duration of AMG 181 exposure, immunogenicity, RO, and the elevation in CD4+ central memory cell count were correlated.

Conclusions: AMG 181 has PK/PD, pharmacology and immunogenicity characteristics in monkeys that are suitable for further development in patients with inflammatory bowel disease.