Estimation of Clearance and Bioavailability of Therapeutic Monoclonal Antibodies from Only Subcutaneous Injection Data in Humans Based on Comprehensive Analysis of Clinical Data.

ABSTRACT

INTRODUCTION: Theoretically, the separate estimation of clearance (CL) and bioavailability (F) requires both intravenous and extravascular injection data. This study investigated whether CL and subcutaneous F of therapeutic monoclonal antibodies (mAbs) in humans can be separately estimated from subcutaneous injection data only. METHODS: First, the geometric mean of linear pharmacokinetic parameters (CL, intercompartmental CL [Q], volume of distribution in the central compartment [Vc], and volume of distribution in the peripheral compartment [Vp]) after intravenous injection for mAbs in humans that have been reported in public data sources was estimated from 103 mAbs with linear pharmacokinetics and 44 mAbs with nonlinear pharmacokinetics. Next, we estimated the CL and F of 25 mAbs with linear pharmacokinetics from plasma/serum mAb concentration-time profiles after subcutaneous injection in humans by fixing the geometric mean of Q, Vc, and Vp based on the public data. Moreover, the plasma/serum concentration-time profile of 25 mAbs after intravenous injection was simulated using the estimated CL and the geometric mean of Q, Vc, and Vp. RESULTS: There were no significant differences in parameters among subclasses (immunoglobulin [Ig] G1, 2, and 4) or in linearity (derivation from linear and nonlinear pharmacokinetics). Using only subcutaneous injection data, we successfully estimated the CL of 23/25 mAbs (92%) and F of all 25 mAbs (100%) within 1.5-fold of the observed value. Moreover, overall, the simulated concentration-time profiles were largely consistent with observed data (90.8% within 1.5-fold of the observed values). CONCLUSIONS: This approach does not require intravenous injection data to separately estimate CL and F after subcutaneous injection in humans and can therefore accelerate the clinical development of mAbs.