1086. A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model that a priori Predicts Intramuscular (IM) Pharmacokinetics of ADG20: an Extended Half-life Monoclonal Antibody Being Developed for the Treatment and Prevention of Coronavirus Disease (COVID-19)
Authors: Van Wart Scott A , Tarbell Evan D , Mager Donald E , Shah Dhaval K , Connolly Lynn E , Ambrose Paul G 
Published: December 2021

Abstract

Background
ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and additional SARS-like CoVs with pandemic potential and an extended half-life. A QSP/PBPK model was constructed using ADG20-specific physiochemical properties and published non-human primate (NHP) and human PK data for other antibodies; it was used to a priori predict and confirm NHP and human PK.

Methods
An existing QSP/PBPK model was modified to include 3 distinct lung sub-compartments: upper airway, lower airway, and alveolar tissue (Figure A). Each sub-compartment (Figure B) contained an epithelial lining fluid (ELF) space (Figure B). The model was fit separately to digitized NHP and human serum PK data for 7 extended half-life antibodies to estimate the apparent neonatal Fc receptor (FcRn) binding affinity (KD,FcRn) and bioavailability by drug. Nasopharyngeal swab (upper airway) and lung (lower airway) ELF PK data from 4 additional antibodies were used to optimize a single rate constant for transcytosis in lung. Patches of positive charge was a covariate on the rate of pinocytosis of antibody entry and exit from the endosomal space (Figure B). Observed NHP (ADG20 10 mg/kg IM) and human (ADG20 300 mg IM) PK data collected over the initial 21 days post dose were compared with model forecasts from a 1000-iteration simulation.

Results
The distribution of fitted NHP KD,FcRn provided accurate predictions of NHP serum PK data (Figure C). NHP ADG20 KD,FcRn was optimized to be 35.7 nM and human ADG20 KD,FcRn (9.55 nM) was derived using a mean NHP:human KD,FcRn ratio of 3.74 across antibodies. Model-based simulated human serum PK data using inter-subject variability from NHP and actual weight distribution from an ongoing Phase 1 study aligned with initial 21-day data (Figure D). Using an adult CDC weight distribution (45–150 kg), the simulated median exceeded 74 days.

Conclusion
The QSP/PBPK model a priori predicted NHP and human ADG20 PK. This innovative QSP-based modeling and simulation approach enabled the evaluation of candidate dose regimens prior to the availability of PK data, supporting the rapid advancement of the ADG20 clinical program during the COVID-19 pandemic.
Figure. Overview of the QSP/PBPK model

(A) Tissue-level diagram. (B) Cellular-level diagram specifically for the upper airway, lower airway, and alveolar spaces within the lung. (C) Predicted median ADG20 concentration in NHP serum following a single ADG20 10 mg/kg IM dose with observed NHP ADG20 concentration data overlaid (black dots). The shaded area represents the 90% prediction interval. (D) Predicted median human serum and ELF PK in humans following a single ADG20 300 mg IM dose with observed human serum (red line) ADG20 concentration data overlaid (black dots), ELF upper airway (blue line), and ELF lower airway (gold). The shaded area represents the 90% prediction interval. CLup, rate of pinocytosis of antibody entry and exit from the endosomal space; CLup_epi, rate of pinocytosis of antibody entry and exit from the epithelial space; FR, fraction of FcRn bound antibody that recycles to the vascular space; L, lymphatic flow rate; LG, large, kdeg, degradation constant; koff, first-order dissociation rate constant of antibody from FcRn; kon, second-order association rate constant for binding of antibody to FcRn; Q, blood or tissue flow rate; SM, small.

Disclosures
Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Donald E. Mager, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)