Prediction of clinical pharmacokinetics of AMG 181, a human anti‐ α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases

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 EC 50 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 EC 10 . 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.