Evaluation of Human Pharmacokinetics, Therapeutic Dose and Exposure Predictions Using Marketed Oral Drugs

Abstract

In this article approaches to predict human pharmacokinetics (PK) are discussed and the capability of the exemplified methodologies to estimate individual PK parameters and therapeutic dose for a set of marketed oral drugs has been assessed. For a set of 63 drugs where the minimum efficacious concentration (MEC) and human PK were known, the clinical dose was shown to be well predicted or in some cases over-estimated using a simple one-compartment oral PK model. For a subset of these drugs, in vitro potency against the primary human targets was gathered, and compared to the observed MEC. When corrected for plasma protein binding, the MEC of the majority of compounds was < or=3 fold over the respective in vitro target potency value. A series of in vitro and in vivo experiments were conducted to predict the human PK parameters. Metabolic clearance was generally predicted well from human hepatocytes. Interestingly, for this compound set, allometry or glomerular filtration rate (GFR) ratio methods appeared to be applicable for renal CL even where CL(renal) > GFR. For approximately 90% of compounds studied, the predicted CL using in vitro-in vivo (IVIV) extrapolation together with a CL(renal) estimate, where appropriate, was within 2-fold of that observed clinically. Encouragingly volume of distribution at steady state (V(ss)) estimated in preclinical species (rat and dog) when corrected for plasma protein binding, predicted human V(ss) successfully on the majority of occasions--73% of compounds within 2-fold. In this laboratory, absorption estimated from oral rat PK studies was lower than the observed human absorption for most drugs, even when solubility and permeability appeared not to be limiting. Preliminary data indicate absorption in the dog may be more representative of human for compounds absorbed via the transcellular pathway. Using predicted PK and MEC values estimated from in vitro potency assays there was a good correlation between predicted and observed dose. This analysis suggests that for oral therapies, human PK parameters and clinical dose can be estimated from a consideration of data obtained from in vitro screens using human derived material and in vivo animal studies. The benefits and limitations of this holistic approach to PK and dose prediction within the drug discovery process are exemplified and discussed.

Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 670 Drug Compounds

“…For VD ss , a large proportion of the values (approximately 42%) falls within total body water (0.7 l/kg). Only a small subset of these drugs was confined to blood (or plasma) volume, with a value close to the generally accepted distribution volume of albumin, or 0.1 l/kg (McGinnity et al, 2007 …”

“…Previous reports have focused on prediction methods that utilize animal pharmacokinetic data (Caldwell et al, 2004;Ward and Smith, 2004a,b;Jolivette and Ward, 2005;Evans et al, 2006;Mahmood et al, 2006;Martinez et al, 2006;Tang and Mayersohn, 2006;Fagerholm, 2007;McGinnity et al, 2007) and in vitro data (Obach et al, 1997;Lombardo et al, 2002Lombardo et al, , 2004Nestorov et al, 2002;Riley et al, 2005;Grime and Riley, 2006). Recently, the availability of computational chemistry methodologies has increased, and these have been applied to the prediction of human pharmacokinetics and/or general absorption-distribution-metabolism-excretion-toxicology properties (Cruciani et al, 2005;Ghafourian et al, 2006;Gleeson et al, 2006;Lombardo et al, 2006;Gleeson, 2007;Gunturi and Narayanan, 2007;Norinder and Bergstroem, 2007).…”

The Development, Characterization, and Application of an OATP1B1 Inhibition Assay in Drug Discovery

“…To this end, Drug Metabolism and Pharmacokinetics departments have spent considerable effort in developing suitable strategies to mitigate drug failure attributed to suboptimal human pharmacokinetics (McGinnity et al, 2007;Beaumont and Smith, 2009). …”

Species Differences in Distribution and Prediction of HumanVssfrom Preclinical Data

“…Unfortunately, their analysis of 103 compounds did not consider potential species differences in plasma protein binding. Other studies have examined single-or multiple-species scaling based on the assumption of V ss,u or f ut equivalency across species using proprietary compounds, with limited species, or only having oral half-life data available in humans for comparison (Obach et al, 1997;McGinnity et al, 2007;Hosea et al, 2009). In such studies, scaling V ss from rats or dogs is proposed to be more accurate (Hosea et al, 2009;Sui et al, 2010), depending on the study.…”