Prof. Leslie Benet – Approaching the Holy Grail in Drug Disposition: IVIVE Barriers

  • Extensive studies have been run to predict in vivo drug clearance, initially drug metabolism but now transporter and transporter-enzyme interplay disposition characteristics, from in vitro human liver parameters with little success. Numerous studies have evaluated the precision medicine potential in humans for metabolic markers, both drugs (so called “drug cocktails”) and endogenous substances, to quantitatively predict clearance and changes in clearance due to inhibition or induction for therapeutic agents, also with little success. And we don’t know why. Presently employed methodologies using human liver tissue in general markedly under-predict (on average @ 9-fold) in vivo metabolic clearance, but not uniformly from drug to drug. Surprisingly, the theoretical basis of the methodology universally employed for these predictions has not been evaluated. Examination of IVIVE predictions reveal that the liver is assumed to function as a homogeneous system, rather than a heterologous environment composed of both aqueous and lipid components into which drugs distribute differentially. We have derived a new theoretical relationship that includes a term Rss,uu, the ratio of the steady-state unbound drug concentration in vivo in the hepatocyte water in contact with the enzymes to the steady-state unbound concentration in the whole liver. Rss,uu varies significantly from drug to drug and thus no universal IVIVE scaling factor will give successful predictions. Furthermore, it must be recognized that the ratio of in vivo liver enzymes to microsomal liver enzymes used in the presently employed IVIVE methodology will most likely not be the same as the ratio of the in vivo liver transporter protein to in vitro hepatocyte transporter protein, and thus for the same drug the Rss,uu for transporter mediated disposition may not equal the Rss,uu for enzymatic mediated disposition. Therefore, the insertion of transport parameters into the liver well-stirred model hepatic equation for metabolism and biliary excretion may only be accurate at the boundary conditions.  Here we maintain that IVIVE predictions vary from drug to drug due to differences in drug distribution, not seen in vitro, which are an inherent component of in vivo clearance measures. The Holy Grail in drug disposition, successful IVIVE extrapolations and using in vivo drug and endogenous markers to predict pharmacokinetics, will only be approached when these characteristics are recognized.

  • Prof. Leslie Benet

    Leslie Z. Benet, Ph.D.

     Dr. Benet, Professor and former Chairman (1978-1998) of Bioengineering and Therapeutic Sciences, University of California San Francisco (UCSF), received his AB, BS and MS from the University of Michigan, and PhD from UCSF.  He has received nine honorary doctorates, five from Europe and four from the US, most recently the University of Lisbon in 2016. Dr. Benet served as President of the Academy of Pharmaceutical Sciences (1985) and in 1986 was a founder and first President of the American Association of Pharmaceutical Scientists.  In 1987 he was elected to membership in the National Academy of Medicine of the US National Academy of Sciences.  In 1993-4 he served as President of the American Association of Colleges of Pharmacy, from 1996-2000 as Chair of the International Pharmaceutical Federation (FIP) Board of Pharmaceutical Sciences and from 2006-2012 as Chair of the FIP Foundation for Education and Research. Recently among his many honors were dedication of the September 2012 issue of Pharmaceutical Research, the 2013 APhA Ebert Prize, dedication of the September 2013 issue of Journal of Pharmaceutical Sciences, selection for the 2013 AAPS Journal Manuscript Award, ISSX North American Achievement Award in 2015, and the Remington Honor Medal of APhA in 2016, the highest award in American Pharmacy.  Dr. Benet has published over 550 scientific articles and book chapters, holds 12 patents and served as editor of 7 books.  He is listed by Thompson Reuters among the most highly cited pharmacologists worldwide with his peer reviewed publications being referenced on more than 24,000 occasions. He serves as Chairman of the Optivia Scientific Advisory Board.

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