The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development

Abstract

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.

Figure 1

The reasons for failure of drug development programmes by the seven UK-based pharmaceutical companies in the period 1964–1985 [4]

Figure 2

Modelled pharmacokinetic profile of a novel chemical entity with consideration of free drug exposure relative to projected efficacy levels (based on, e.g. receptor occupancy) and safety threshold (based on, e.g. level at which QT prolongation is anticipated)

Figure 3

Variation in area under the plasma concentration–time curve (AUC) following a single oral dose of the CYP2D6 substrate and calcium channel antagonist (UK-84,149) to human volunteers [49] Individuals characterised as poor metabolizers for CYP2D6 indicated by asterisks

Figure 4

Mean C_max (n = 8 or 9) from single oral solution doses of 10, 30, 100, 200, 400 and 800 mg of the PDE5 inhibitor (UK-343,664) to human volunteers. The solid line shows the line of identity based on the 10-mg dose [66]