Abstract
In vivo pharmacokinetics (PK) studies using mice and monkeys are the main approaches for evaluating and predicting the PK of antibodies, and there is a strong demand for methods that do not require animal experiments. In this work, we focused on quantitatively predicting the nonlinear PK of an antibody based on cell-based assays. An anti-mouse Fc gamma receptor IIB antibody was used as a model antibody. To determine the PK parameters related to nonspecific elimination in vivo, the plasma concentration profile at 100 mg/kg, at which target-specific clearance is saturated, was analyzed by a 2-compartment model. To estimate the parameters related to target-specific elimination, the Michaelis–Menten constant (Km) and the maximum elimination rate (Vmax) were determined by an uptake assay using Chinese hamster ovary (CHO) cells expressing the target receptor. Finally, the integration of all of these parameters permitted the PK to be predicted at doses ranging from 1 to 100 mg/kg regardless of whether target-specific clearance was saturated or nonsaturated. The findings presented herein show that in vitro assays using target-expressing cells are useful tools for obtaining PK parameters and predicting PK profiles and, in some cases, eliminate the need for in vivo PK studies using experimental animals.
Highlights
In vivo pharmacokinetics (PK) studies using mice and monkeys are the main approaches for evaluating and predicting the PK of antibodies, and there is a strong demand for methods that do not require animal experiments
To evaluate PK profiles, the antibody was administered to mice at doses ranging from 1 to 100 mg/kg, and the plasma concentration–time profile of the antibody was determined (Fig. 2a)
Clearance was drastically slower at doses approaching 100 mg/kg than at the minimum dose (1 mg/kg) and reached a plateau at 100 mg/kg. This suggests that target-specific clearance was saturated at 100 mg/kg and that at a higher dose, clearance was largely explained by nonspecific decay
Summary
In vivo pharmacokinetics (PK) studies using mice and monkeys are the main approaches for evaluating and predicting the PK of antibodies, and there is a strong demand for methods that do not require animal experiments. Human FcRn transgenic mice and cynomolgus monkeys are frequently used to reveal the PK of candidate antibodies in vivo, and it is widely accepted that empirical approaches, such as simple allometric scaling, can reliably predict the human linear PK of an antibody that does not show target-dependent e limination[4,5] This approach involves the sacrifice of many experimental animals. Cell-based assays such as FcRn-mediated transcytosis assays have been developed to predict the half-life of an antibody, but they can only be used to rank candidate antibodies by half-life[9,10,11,12] For these reasons, an in vivo-based approach would be the most efficient strategy for evaluating the PK of an antibody not cleared by target-dependent elimination in animals and predicting it in humans. It is clear that alternative methods to in vivo PK studies are needed
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