Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned?
The pharmacokinetics (PK) of therapeutic antibodies is determined by target and non-target mediated mechanisms. These antibody-specific factors need to be considered during prediction of human PK based upon preclinical information. Principles of allometric scaling established for small molecules using data from multiple animal species cannot be directly applied to antibodies. Here, different methods for projecting human clearance (CL) from animal PK data for 13 therapeutic monoclonal antibodies (mAbs) exhibiting linear PK over the tested dose ranges were examined: simple allometric scaling (CL versus body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent and scaling from only cynomolgus monkey PK data. A better correlation was obtained between the observed human CL and the estimated human CL based on cynomolgus monkey PK data and an allometric scaling exponent of 0.85 for CL than other scaling approaches. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 0.85 for CL and 1.0 for volume of distribution. In conclusion, we expanded our previous work and others and further confirmed that PK from cynomolgus monkey alone can be successfully scaled to project human PK profiles within linear range using simplify allometry and Dedrick plots with fixed exponent.
Deng
Rong
R
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, CA, USA. rdeng@gene.com
Iyer
Suhasini
S
Theil
Frank-Peter
FP
Mortensen
Deborah L
DL
Fielder
Paul J
PJ
Prabhu
Saileta
S
D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D051381:Rats; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C485206:pertuzumab