Animal versus human oral drug bioavailability: do they correlate?

Abstract

Oral bioavailability is a key consideration in development of drug products, and the use of preclinical species in predicting bioavailability in human has long been debated. In order to clarify whether any correlation between human and animal bioavailability exist, an extensive analysis of the published literature data was conducted. Due to the complex nature of bioavailability calculations inclusion criteria were applied to ensure integrity of the data. A database of 184 compounds was assembled. Linear regression for the reported compounds indicated no strong or predictive correlations to human data for all species, individually and combined. The lack of correlation in this extended dataset highlights that animal bioavailability is not quantitatively predictive of bioavailability in human. Although qualitative (high/low bioavailability) indications might be possible, models taking into account species-specific factors that may affect bioavailability are recommended for developing quantitative prediction.

Keywords: Drug development; First in man pharmacokinetics; Oral drug absorption.

Graphical abstract

Fig. 1

Plot of oral bioavailability (F) in animal species vs. oral bioavailability in humans (in percentage). Diamonds are for mouse, circles for rat, and triangles for dog and squares for non-human primates (NHP).

Fig. 2

Plots for the linear regression analysis by separated by species (in percentages), the coefficient of determination (R²) for the linear regression are shown in each plot. (a) Mouse F vs. human F_; (b) Rat F vs. human F_; (c) Dog F vs. human F and (d) Non-human primates (NHP) F vs. human F.

Fig. 3

Box plots of median animal/human bioavailability ratios (R_A/H) and interval between animal and human oral bioavailability. Triangles indicate 95% confidence interval (CI) for the median values; Dashed line (- - -), indicate the upper limit for outliers representation.

Fig. 4

Plots for the linear regression analysis by separated by ion class (in percentages), the coefficient of determination (R²) for the linear regression are shown in each plot. (a) Mouse F vs. human F_; (b) Rat F vs. human F_; (c) Dog F vs. human F and (d) Non-human primates (NHP) F vs. human F.

Fig. 5

Plot of the linear regression analysis for the general dataset, animal vs. human oral bioavailability. Diamonds are for mouse, circles for rat, and triangles for dog and squares for non-human primates (NHP). Solid line (–), linear regression line; Pointed line (⋯), 95% confidence interval (CI) for mean response; Dashed line (- - -), 95% prediction interval (PI) for a future value.

Fig. 6

Plots for the linear regression analysis by classified by species (in percentages), the coefficient of determination (R²) for the linear regression are shown in each plot. (a) Mouse F vs. human F_; (b) Rat F vs. human F_; (c) Dog F vs. human F and (d) Non-human primates (NHP) F vs. human F_. Solid line (–), linear regression line; Pointed line (⋯), 95% confidence interval (CI) for mean response; Dashed line (- - -), 95% prediction interval (PI) for a future value.