Rat as a Predictive Model for Human Clearance and Bioavailability of Monoclonal Antibodies

Abstract

Background: The prediction of human clearance (CL) and subcutaneous (SC) bioavailability is a critical aspect of monoclonal antibody (mAb) selection for clinical development. While monkeys are a well-accepted model for predicting human CL, other preclinical species have been less-thoroughly explored. Unlike CL, predicting the bioavailability of SC administered mAbs in humans remains challenging as contributing factors are not well understood, and preclinical models have not been systematically evaluated.

Methods: Non-clinical and clinical pharmacokinetic (PK) parameters were mined from public and internal sources for rats, cynomolgus monkeys, and humans. Intravenous (IV) and SC PK was determined in Sprague Dawley rats for fourteen mAbs without existing PK data. Together, we obtained cross-species data for 25 mAbs to evaluate CL and SC bioavailability relationships among rats, monkeys, and humans.

Results: Rat and monkey CL significantly correlated with human CL and supported the use of species-specific exponents for body-weight-based allometric scaling. Notably, rat SC bioavailability significantly correlated with human SC bioavailability, while monkey SC bioavailability did not. Bioavailability also correlated with clearance.

Conclusions: The rat model enables an early assessment of mAb PK properties, allowing discrimination among molecules in the discovery pipeline and prediction of human PK. Importantly, rat SC bioavailability significantly correlated with human SC bioavailability, which has not been observed with other species. Rats are cost-effective and efficient relative to monkeys and provide a valuable tool for pharmacokinetic predictions in therapeutic antibody discovery.

Keywords: allometric scaling; bioavailability; clearance; monoclonal antibody; pharmacokinetics; rat.

Figure A1

(a) Weight-normalized clearance for all mAbs in the dataset across species. (b) Subcutaneous bioavailability (%) for all mAbs in the dataset across species. Data are presented as mean ± standard deviation.

Figure 1

Weight-normalized clearance (CL) relationships between humans and pre-clinical species. (a) CL in humans versus CL in monkeys for 22 mAbs; (b) CL in humans versus CL in rats for 23 mAbs. Solid black lines represent the unity line, while dashed lines represent 0.5 and 2-fold change from the unity line.

Figure 2

Goodness-of-fit plots and scaled human clearance (CL) for monkey-to-human (a–c) and rat-to-human (d–f) allometric CL models. Observed versus predicted CL in monkeys (a) and humans (b) from the monkey-to-human model. (c) Observed human CL versus human CL scaled from monkeys using an allometric exponent of 0.84. Observed versus predicted CL in rats (d) and humans (e) from the rat-to-human model. (f) Observed human CL versus human CL scaled from rats using an allometric exponent of 0.92. Solid lines represent the unity line, while dashed lines represent 2-fold change in slope from the unity line.

Figure 3

Subcutaneous bioavailability (SC%F) relationships between humans and pre-clinical species. (A) SC%F in humans versus SC%F in monkeys for 14 mAbs. (B) SC%F in humans versus SC%F in rats for 13 mAbs. Solid black lines represent the unity line, while dashed black lines represent a 1.5-fold change in slope from the unity line. Dashed blue lines and equations represent linear regression of the data points.

Figure 4

Correlation analysis between weight-normalized clearance (CL) and subcutaneous bioavailability (SC%F) in (A) humans, (B) monkeys, and (C) rats. Linear regression lines and analyses are shown on each graph.