Scaling Factors for the Extrapolation of In Vivo Metabolic Drug Clearance From In Vitro Data: Reaching a Consensus on Values of Human Micro-somal Protein and Hepatocellularity Per Gram of Liver

Abstract

Reported predictions of human in vivo hepatic clearance from in vitro data have used a variety of values for the scaling factors human microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of liver, generally with no consideration of the extent of their inter-individual variability. We have collated and analysed data from a number of sources, to provide weighted meangeo values of human MPPGL and HPGL of 32 mg g-1 (95% Confidence Interval (CI); 29-34 mg.g-1) and 99x10(6) cells.g-1 (95% CI; 74-131 mg.g-1), respectively. Although inter-individual variability in values of MPPGL and HPGL was statistically significant, gender, smoking or alcohol consumption could not be detected as significant covariates by multiple linear regression. However, there was a weak but statistically significant inverse relationship between age and both MPPGL and HPGL. These findings indicate the importance of considering differences between study populations when forecasting in vivo pharmacokinetic behaviour. Typical clinical pharmacology studies, particularly in early drug development, use young, fit, healthy male subjects of around 30 years of age. In contrast, the average age of patients for many diseases is about 60 years of age. The relationship between age and MPPGL observed in this study estimates values of 40 mg.g-1 for a 30 year old individual and 31 mg.g-1 for a 60 year old individual. Investigators may wish to consider the reported covariates in the selection of scaling factors appropriate for the population in which estimates of clearance are being predicted. Further studies are required to clarify the influence of age (especially in paediatric subjects), donor source and ethnicity on values of MPPGL and HPGL. In the meantime, we recommend that the estimates (and their variances) from the current meta-analysis be used when predicting in vivo kinetic parameters from in vitro data.

Using a Vancomycin PBPK Model in Special Populations to Elucidate Case‐Based Clinical PK Observations

“…In this calculation, 1,736.96 g of liver weight21 and 126.27 million cells/g liver22 were used as representative values of healthy volunteers.…”

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

“…Furthermore, indinavir was excluded from the oral dataset as the high dose at which it is administered (400 -800 mg) was shown to significantly reduce its systemic clearance (Yeh et al, 1999). The unbound CLu int from all HLM pools investigated were scaled using the mean microsomal recovery of 40 mg of protein/g of liver (Barter et al, 2007) and a liver weight of 21.4 g of liver/kg. Determination of In Vitro Permeability.…”

Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

“…This number needs to be put into context with the direct measurement of 500,000 CD81 copies per cell on primary human hepatocytes (Table S2): assuming a liver cellularity of 100 million cells per g 22 and a liver volume of 150 ml for a 5 kg monkey, 19 the liver alone is estimated to contribute approximately 2.5 nmol/kg to the total target load. This model therefore predicts a significant volume of CD81 outside of the liver, consistent with CD81 expression analysis showing high CD81 levels in non-hepatic cells.…”