In vitro-in vivo extrapolation of clearance: modeling hepatic metabolic clearance of highly bound drugs and comparative assessment with existing calculation methods.
In vitro-in vivo extrapolation (IVIVE) is an important method for estimating the hepatic metabolic clearance (CL) of drugs. This study highlights a problematic area observed when using microsomal data to predict in vivo CL of drugs that are highly bound to plasma proteins, and further explores mechanisms for human CL predictions by associating additional processes to IVIVE disconnect. Therefore, this study attempts to develop a novel IVIVE calculation method, which consists of adjusting the binding terms in a well-stirred liver model. A comparative assessment between the IVIVE method proposed here and previously published methods of Obach (1999. Drug Metab Dispos 27:1350-1359) and Berezhkovskiy (2010. J Pharm Sci 100:1167-1783) was also performed. The assessment was confined by the availability of measured in vitro and in vivo data in humans for 25 drugs highly bound to plasma proteins, for which it can be assumed that metabolism is the major route of elimination. Here, we argue that a difference in drug ionization and binding proteins such as albumin (AL) and alpha-1-acid glycoprotein (AAG) in plasma and liver also needs to be considered in IVIVE based on mechanistic studies. Therefore, converting unbound fraction in plasma to liver essentially increased the predicted CL values, which resulted in much more accurate estimates of in vivo CL as compared with the other IVIVE methods tested. The impact on CL estimate was more apparent for drugs binding to AL than to AAG. This is a mechanistic rational for explaining a considerable proportion of the divergence between previously estimated and observed CL values. Human CL was predicted within 1.5-fold, twofold, and threefold of the observed CL for 84%, 96%, and 100% of the compounds, respectively. Overall, this study demonstrates a significant improvement in the mechanism-based prediction of metabolic CL for these 25 highly bound drugs from in vitro data determined with microsomes, which should facilitate the application of physiologically based pharmacokinetic (PBPK) models in drug discovery and development.
Consultant, 4009 Sylvia Daoust, Québec City, Québec G1X 0A6, Canada. patrick-poulin@videotron.ca
Patrick
P
Poulin
Jane R
JR
Kenny
Cornelis E C A
CE
Hop
Sami
S
Haddad
D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008962:Models, Theoretical; D010599:Pharmacokinetics