title: Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases.
abstract: The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two-compartment model with parallel linear and target-mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An E max PD model was used to relate AMG 181 concentration and free α 4 β 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg(-1) in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 β 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day(-1) and 2900 mL, respectively. The estimated EC50 for free α 4 β 7 receptor was 14 ng·mL(-1). At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 β 7 receptor EC10. Predictions for both C max and AUC matched with those observed in the first-in-human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc. Thousand Oaks, California.
authors.forename: John A
authors.initials: JA
authors.lastname: Wisler
authors.affiliation: Medical Sciences, Amgen Inc. Seattle, Washington.
authors.forename: William A
authors.initials: WA
authors.lastname: Rees
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Prince
authors.affiliation: Medical Sciences, Amgen Inc. Seattle, Washington.
authors.forename: Kai O
authors.initials: KO
authors.lastname: Reynhardt
authors.affiliation: Inflammation Discovery Research, Amgen Inc. Thousand Oaks, California.
authors.forename: Hailing
authors.initials: H
authors.lastname: Hsu
authors.affiliation: Medical Sciences, Amgen Inc. Thousand Oaks, California.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Global Development, Amgen Inc. South San Francisco, California.
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Borie
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington.
authors.forename: David H
authors.initials: DH
authors.lastname: Salinger
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington.
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Pan
keywords: AMG 181; Crohn’s disease; PK/PD predictions; T cells; anti-α4β7; cell trafficking; gut homing; human antibody; inflammatory bowel diseases; ulcerative colitis; α4β7 integrin