Interspecies scaling: prediction of human biliary clearance and comparison with QSPKR

Abstract

The aim of this study was to evaluate the prediction performance of various allometric scaling methods in predicting human biliary clearance (CL(b)) from data in rats or multiple animal species and to compare the prediction performance with that of quantitative structure pharmacokinetic relationship (QSPKR) models. CL(b) data of parent drugs in rats and humans were collected from the literature for 18 compounds. A simple allometric approach was applied to CL(b) or unbound CL(b) using 0.75 or 0.66 as the allometric exponent. For scaling from rat studies alone, the prediction using 0.66 as the exponent was better than that using 0.75, and a better prediction was obtained for unbound CL(b) than CL(b). For a subset of compounds, six multiple-species scaling methods were compared, with the best prediction achieved with the simple unbound CL(b) approach. However, in the absence of protein binding data, the correction with maximum life-span potential (MLP) or 'Rule of exponent' (ROE) method offered the best prediction. Overall, multiple species had better predictability than scaling with the rat alone. Comparison of predicted human CL(b) values using multiple animal species and QSPKR offered similar prediction performance. In conclusion, the results of the present study, although based on limited data, suggested that the prediction for human CL(b) by allometry was greatly improved by the incorporation of protein binding. Human CL(b) prediction using rat data alone was not satisfactory. Additionally, QSPKR provides an alternative approach to allometry for the prediction of human biliary clearance.

Species Differences in Biliary Clearance and Possible Relevance of Hepatic Uptake and Efflux Transporters Involvement

“…Although this is only an emerging perspective based on an analysis of the available literature, we believe it to be a useful indicator to Drug Discovery DMPK scientists handling rat biliary clearance data in a preclinical setting when rapid but educated decisions are required. Toward drug candidate selection at the preclinical /clinical development interface, biliary clearance data from multiple species will of course help in minimizing the risk of a poor human prediction (Morris et al, 2012) and a pharmacokinetic modeling/simulation approach, taking into account all the relevant processes and in vitro data to facilitate more precise predictions of human biliary clearance should be a strong consideration (Kusuhara and Sugiyama 2010;Swift et al, 2010). Future work to further understanding should certainly involve a detailed package of in vitro work with the drugs discussed here to define the active uptake intrinsic clearance values in rat, dog, and human hepatocytes and to more fully define the transporter information.…”

“…Recently a database of 18 drugs having known rat and human biliary clearance was published, representing the most extensive dataset to date (Morris et al, 2012). From this it was evident that, when considering unbound clearance (corrected for plasma protein binding), simple allometry using an exponent of 0.66 gave reasonable human predictions for some drugs, but for others rat overstimulated human biliary clearance by an excess of one order of magnitude.…”

“…To investigate this further, we compiled an even more extensive rat and human biliary clearance data set than that of Morris et al (2012) for 22 drugs of all charge types and several different therapeutic classes. For nine of the drugs, it was also possible to find data for dog biliary clearance.…”

Interspecies scaling of biliary excreted drugs: prediction of human clearance and volume of distribution

“…It should be noted that the correction factors are only applicable to the total clearance of biliary excreted drugs, not to the biliary clearance of the drugs (36) . There is no evidence that the prediction of human volume of distribution, especially V ss of drugs that are biliary excreted, is affected because of the biliary excretion of the drug.…”

“…The mean bileto-plasma concentration ratio of ticarcillin and clavulanic acid was 5:1 and 0.43:1, respectively (35) . Percent of biliary clearance to total clearance: ceftriaxone in rat, dog, and man, 18, 46, and 28, respectively; doxorubicin in mice, rat, rabbit, monkey, dog, and man, 6, 51, 3, 4, 8, and 16, respectively; digoxin in mice, rat, dog, and man, 60, 13, 44, and 64, respectively (36) . Amount excreted as unchanged drug or conjugated metabolite not known for ragaglitazar and muraglitazar.…”