Clinical development of a drug candidate and pharmacological evidence by Darren Wogman

Critically discuss the pharmacological evidence that would be needed to justify clinical development: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) describe the aims of preclinical testing in their M3 guidance as “[The characterisation of the] toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility..[and] to characterise potential adverse effects” (ICH, 2009).

Non-clinical studies ensure that the Investigational medicinal product (IMP) pharmacokinetic (PK) and pharmacodynamic (PD) properties can be determined. Bioavailability studies, mechanisms of ADME (absorption, distribution, metabolism and elimination), safety pharmacology studies, toxicity studies and the assessment of potential genotoxicity, mutagenicity and carcinogenicity are all critical to carry out (Andrade et al., 2016).

The drug half-life reflects the distribution and elimination of the drug and is especially important in drugs administered orally due to first-pass metabolism by the liver. Required PK data would be maximal IMP blood-plasma concentration (Cmax), the time at which this took place (Tmax) and the area under the curve (AUC). When these data are plotted the systemic exposure of IMP can be determined. Clearance rates and volume of distribution can be calculated in order to better inform decision making when determining doses in humans. As drug metabolites may impart a pharmacological effect, the route of metabolism must be understood and characterised (Attia, 2010). If the drug is excreted by the renal pathway, it might be prudent to carry out further investigation into the impact on the kidney. As the proposed IMP will be for long-term, chronic use any detrimental impacts of metabolic or excretory organs fully elucidated.

The mass of the IMP should be sufficient to cross the blood brain barrier (BBB). As well as lipid solubility, molecular weight is critical to a substance’s ability to permeate the BBB. The literature suggests a maximal molecular weight of >500 Da (Banks, 2009). However, in order to establish that the proposed drug reaches its target (namely, the brain), a radiolabelled version of the drug can be administered, brain imaging techniques then allow for the determination of the drug or metabolite presence in the target tissue. Radioligand-binding studies of cells expressing human serotonin transporters, for example could be carried out to show IMP affinity to target receptors. (Owens et al., 1997, Owens, Knight and Nemeroff, 2001).

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Affinity selection-mass spectrometry (AS-MS) and Protein binding assays can determine further binding locations of IMP to receptors and provide indicative information on the likely efficacy of the candidate compound. (Pollard, 2010, Annis et al., 2007). IMP-plasma protein binding can infer the likely distribution of the drug in the systemic circulation and provide a measure of how easily the target is reached. Binding potency can predict clinical efficacy and likely adverse effects (Ye, Nagar and Korzekwa, 2016). These studies also provide a route to determine bioavailability. Absorption mechanisms of pharmaceutical products can be similar across species. Although metabolic process such as, first-pass metabolism account for some observed differences (Voortman and Paanakker, 1995). Data from these studies are extrapolated to determine the in-vivo blood plasma concentration needed for elicit a PD effect in humans. Mechanism of action (MoA) can be further elucidated buy the use of animal models. The most commonly used will be discussed below.