Integration of in Vitro Data into Allometric Scaling to Predict Hepatic Metabolic Clearance in Man: Application to 10 Extensively Metabolized Drugs

Abstract

In this study, we investigated rational and reliable methods of using animal data to predict in humans the clearance of drugs which are mainly eliminated through hepatic metabolism. For 10 extensively metabolized compounds, adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro dramatically improved the predictions of human clearance compared to the approach in which clearance is directly extrapolated using body weight. Using hepatocyte data to normalize the in vivo clearances led to lower median deviations between the observed and predicted clearances in man compared to the approach normalizing data with brain weight (30-40% vs 60-80%, respectively). In addition, the approach integrating in vitro data appeared to be superior with respect to the range of deviations: approximately 2-fold underestimation, in the worst case, was observed by using in vitro data, whereas normalizing data by brain weight led to up to 10-fold underestimation of clearance in man. In addition, the integration of in vitro data provides a more rational basis to predict the metabolic clearance in man and may be applicable to compounds undergoing phase I and phase II metabolism as well.

A Unified Model for Predicting Human Hepatic, Metabolic Clearance From in Vitro Intrinsic Clearance Data in Hepatocytes and Microsomes

“…It is widely accepted that simple allometric methods are generally not suitable for predicting human clearance for compounds, which exhibit low to intermediate extraction via metabolism (Lave et al, 1997a;Nagilla and Ward, 2004). In vitro-in vivo scaling of metabolic clearance has received much attention (Houston, 1984;Houston and Carlile, 1997;Iwatsubo et al, 1997;Naritomi et al, 2001) and also provides input for physiologically based pharmacokinetic models (Theil et al, 2003).…”

“…Existing methods for the prediction of drug clearance in humans involve the use of in vitro human metabolic stability (intrinsic clearance, CL int ) data (Iwatsubo et al, 1997), consideration of preclinical animal data (Boxenbaum, 1982), or a combination of these approaches (Lave et al, 1997a;Naritomi et al, 2001). In vitro drug metabolism kinetic parameters can provide an estimate of in vivo CL int via "scaling" with established biological scaling factors (SFs) e.g., hepatocellularity for isolated hepatocytes, or a SF for microsomes based on incomplete microsomal recovery from human liver tissue using the cytochrome P450 (P450) content in homogenate and microsomes (Houston, 1984).…”

Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance

“…Incubations for metabolite identification were performed in suspension in a 2.5-ml total volume. Vials of hepatocytes were thawed rapidly in a water bath set at 37°C, then diluted with cold Williams E medium (pH 7.4) containing 10% fetal bovine serum (Lave et al, 1997). Cells were isolated by centrifugation and pooled and resuspended in cold Williams E medium buffer at 2 million viable cells/ml.…”

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

“…A similar approach can be undertaken for human CL predictions, although for certain classes of compound there is a lack of correlation between the CLi value derived in vitro using human microsomes or hepatocytes and that Human microdose study of GSK269984A calculated in vivo [43]. Ostensibly, the present data would lend support to other studies that have shown how the prediction of human CL in vivo can be improved by the appropriate incorporation of in vitro data.For example, predictions of human CL based on allometric scaling from pre-clinical in vivo data can be improved by first normalizing in vivo CL values using the respective in vitro CLi values [44], while other investigators have proposed the initial correction of in vitro human CLi using a scaling factor derived from animal studies [45,46]. However, in this current study, the values obtained for GSK269984A CLi in microsomes (rat, dog, primate and human), S9 fractions (rat, dog, primate and human) and hepatocytes (rat, primate and human) were essentially equal across all species [16].…”