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

ABSTRACT 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.