Abstract
These days, there is a lot of emphasis on the prediction of human clearance (CL) from a single species for monoclonal antibodies (mabs). Many studies indicate that monkey is the most suitable species for the prediction of human clearance for mabs. However, it is not well established if rodents (mouse or rat) can also be used to predict human CL for mabs. The objectives of this study were to predict and compare human CL as well as first-in-human dose of mabs from mouse or rat, ormonkey. Four methods were used for the prediction of human CL of mabs. These methods were: use of four allometric exponents (0.75, 0.80, 0.85, and 0.90), a minimal physiologically based pharmacokinetics method (mPBPK), lymph flow rate, and liver blood flow rate. Based on the predicted CL, first-in-human dose of mabs was projected using either exponent 1.0 (linear scaling) or exponent 0.85, and human-equivalent dose (HED) from each of these species. The results of the study indicated that rat or mouse could provide a reasonably accurate prediction of human CL as well as first-in-human dose of mabs. When exponent 0.85 was used for CL prediction, there were 78%, 95%, and 92% observations within a 2-fold prediction error for mouse, rat, and monkey, respectively. Predicted human dose fell within the observed human dose range (administered to humans) for 10 out of 13 mabs for mouse, 11 out of 12 mabs for rat, and 12 out of 15 mabs for monkey. Overall, the clearance and first-in-human dose of mabs were predicted reasonably well by all three species (a single species). On average, monkey may be the best species for the prediction of human clearance and human dose but mouse or rat especially; rat can be a very useful species for conducting the aforementioned studies.
Highlights
In recent years, the prediction of pharmacokinetic (PK) parameters from a single animal species such as rat, dog, or monkey to humans has been gaining momentum for both small and macro-molecules
Since clearance is an important PK parameter, most studies have focused on predicting clearance of drugs from animals to humans
These studies show that the monkey is the most suitable animal species to predict drug clearances in humans
Summary
The prediction of pharmacokinetic (PK) parameters from a single animal species such as rat, dog, or monkey to humans has been gaining momentum for both small and macro-molecules. There is a lot of emphasis on the prediction of human PK parameters, mainly clearance for monoclonal antibodies (mabs) from a single species [1,2,3]. These methods use a fixed exponent on body weight to predict CL of mabs in humans from monkey. Lin et al [2] concluded that exponents 0.85 and 0.9 are needed to predict human clearance for mabs in humans from monkey for soluble antigens as well as membranebound antigens, respectively.
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