Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model.
OBJECTIVE
To examine the across-species scalability of monoclonal antibody (mAb) pharmacokinetics (PK) and assess similarities in tissue distribution across species using a recently developed minimal PBPK (mPBPK) model.


METHODS
Twelve sets of antibody PK data from various species were obtained from the literature, which were jointly and individually analyzed. In joint analysis, vascular reflection coefficients for tissues with either tight (σ 1 ) or leaky endothelium (σ 2 ) were assumed consistent across species with systemic clearance allometrically scaled (CL = a∙BW (b) ). Four parameters (σ 1 , σ 2 , a, and b) were estimated in the joint analysis. In addition, the PK from each species was individually analyzed to assess species similarities in tissue distribution.


RESULTS
Twelve mAb PK profiles were well-captured by the mPBPK model in the joint analysis. The estimated σ 1 ranged 0.690 to 0.999 with an average of 0.908; and σ 2 ranged 0.258 to 0.841 with an average of 0.579. Clearance was reasonably scaled and b ranged 0.695 to 1.27 averaging 0.91. Predictions of plasma concentrations for erlizumab and canakinumab in humans using parameters obtained from fitting animal data were consistent with actual measurements.


CONCLUSIONS
Therapeutic mAbs given IV usually exhibit biexponential kinetics with their distribution properties best captured using physiological concepts. The mPBPK modeling approach may facilitate efforts in translating antibody distribution and overall PK across species.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA.
Jie
J
Zhao
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA.
Yanguang
Y
Cao
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA. wjjusko@buffalo.edu.
William J
WJ
Jusko
D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D014018:Tissue Distribution / Q000502:physiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C541220:canakinumab
allometric scaling; monoclonal antibody; second-generation mPBPK