A Quantitative Prediction Method for the Human Pharmacokinetics of Fc-Fusion Proteins.

Background and objective: Fc fusion is an effective strategy for extending the half-lives of therapeutic proteins. This study aimed to evaluate the applicability of a human pharmacokinetics prediction method for Fc-fusion proteins by extending on reported methods for monoclonal antibodies (mAbs).

Methods: To predict human pharmacokinetic profiles following intravenous (IV) dosing, the pharmacokinetic data for 11 Fc-fusion proteins in monkeys were analysed by two approaches: a species-invariant time method with a range of allometric exponents in clearance (CL, 0.7-1.0) and a two-compartment model reported for mAbs. The pharmacokinetic profiles following subcutaneous (SC) dosing were predicted by simple dose normalisation from monkeys or using the geometric means of the absorption rate constant (Ka) and bioavailability (BA) for mAbs or Fc-fusion proteins in humans and compared.

Results: In the case of IV administration, the area under the curve could be predicted for more than 85% of Fc-fusion proteins within a twofold difference from the observed value using the species-invariant time method (scaling exponent for CL, 0.95). For SC dosing, incorporating the geometric means of absorption parameters for both mAbs (BA 68.2%, Ka 0.287 day^-1) and Fc-fusion proteins (BA 63.0%, Ka 0.209 day^-1) in humans provided better accuracy than simple normalisation from monkeys.

Conclusion: We have successfully predicted the human pharmacokinetic profiles of Fc-fusion proteins for both IV and SC administration within twofold of the observed value from monkey pharmacokinetic data by extending on reported methods for mAbs. This method will facilitate drug discovery and development of Fc-fusion proteins.