Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned?

Abstract

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.

Figure 1

Observed (•) and predicted pertuzumab serum concentration-time profiles [median (−), 2.5%, 97.5% quantile (−−)] in humans normalized by dose. Pertuzumab concentration-time profiles were scaled from cynomolgus monkey using Dedrick approach with exponent of 0.85 and 1 for CL and V, respectively. The predicted CL, V_ss and V_c for pertuzumab obtained by fitting compartmental modeling were 3.39 mL/kg/day, 69.8 mL/kg and 34.36 mL/kg, respectively, which is consistent with the observed values (CL = 3.31 mL/day/kg, V_ss = 70.0 mL/kg and V_c = 40.9 mL/kg).

Figure 2

Accuracy of allometric scaling of human clearance of 13 therapeutic mAbs from observed clearance using various scaling methods [(A) simple allometric scaling, (B) simple allometric scaling with maximum life potential as correction factor; (C) simple allometric scaling with brain weight as correction factor; (D) allometric scaling based on ROE (rule of exponent) for therapeutic Abs; (E) scaling from cynomolgus monkey using a fixed exponent of clearance of 0.85 (validation data set n = 9); (F) scaling from cynomolgus monkey using a fixed exponent of clearance of 0.85 (full data set n = 13)]. No rodent PK studies were conducted for GNE mAb U and GNE mAb W, therefore, only allometric scaling from cynomolgus monkey were performed for these two mAbs. The percent prediction error (%PE) is the difference between the estimated clearance and observed clearance divided by observed or predicted clearance ×100 for over-prediction () and under-prediction (■), respectively. The solid line represents %PE = 0. The dashed lines represent %PE = 100% or −100%.