Quantitative Prediction of Human Pharmacokinetics for Fc‐Engineered Therapeutic Monoclonal Antibodies With Increased <scp>FcRn</scp> Binding Mutations After Subcutaneous Injection

Fc-engineered antibodies (mAbs) enhancing FcRn binding have rapidly expanded in drug discovery and development. Although an approach exists for predicting the pharmacokinetics of Fc-engineered mAbs after intravenous injections in humans, no methodology has been established for predicting pharmacokinetics after subcutaneous injections. This study aimed to establish a methodology for predicting the pharmacokinetics of Fc-engineered mAbs after subcutaneous injections in humans. First, bioavailability (F) and absorption rate constant (k_a) values following subcutaneous injections in humans were collected and analyzed. Then, AUC after subcutaneous injections in humans was predicted using the geometric mean of reported F and allometrically scaled clearance (CL) from cynomolgus monkeys. Next, plasma concentration-time profiles after subcutaneous injections were predicted using the geometric mean of reported F and k_a values and allometrically scaled two-compartment model parameters from cynomolgus monkeys. The geometric mean of reported F for Fc-engineered mAbs in humans was 0.601, lower than that of normal mAbs. The geometric mean of ka was 0.284/day, comparable to normal mAbs. The prediction accuracy of AUC using the geometric mean of F and scaled CL from cynomolgus monkeys was 95.2% within 2-fold of observed values. Furthermore, C_max and T_max after subcutaneous injections showed 94.1% and 70.6% prediction accuracy within 2-fold of observed values, respectively. Overall, 88.4% and 95.3% of whole plasma concentration-time profiles were predicted within 2-fold and 3-fold of observed values, respectively, demonstrating the high prediction accuracy. This methodology, combining fixed absorption parameters with scaled two-compartment model parameters, can significantly support Fc-engineered mAbs development.