Prediction of clinical pharmacokinetics of AMG 181, a human anti‐α4β7 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-α4β7 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 Emax PD model was used to relate AMG 181 concentration and free α4β7 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% α4β7 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 α4β7 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 α4β7 receptor EC10. Predictions for both Cmax 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.