Don K. Walker

A Holistic Strategy for Characterizing the Safety of Metabolites through Drug Discovery and Development

The subject of metabolites in safety testing has had much debate in the recent past and has shown itself to be a complex issue with no simple solutions to providing absolute assurance of drug safety. Much of the attention has focused on the ability to identify metabolites and then demonstrate that their risk has been adequately characterized, either through their exposure in toxicology species or, failing this, by direct safety testing. In this review, we summarize our forward operational strategy that combines the principles summarized in the FDA Guidance, together with discussions at scientific meetings and literature opinions. It is a balance between the primary goal of assuring patient safety with one of reasonable investment. A key principle in striking this balance is to build stepwise information on metabolites through the drug discovery and development continuum. This allows assessments to be made from early nonclinical studies onward as to whether or not metabolite safety is underwritten by exposure in toxicology species. This strategy does not require absolute quantitation of the metabolites in early clinical trials but relies upon comparison of relative exposures between animals and humans using the capabilities of modern analytical techniques. Through this strategy, human disproportionate metabolites can be identified to allow a decision regarding the need for absolute quantitation and direct safety testing of the metabolite. Definitive radiolabeled studies would be initiated following proof of pharmacology or efficacy in humans, and nonclinical safety coverage would be adequately assessed prior to large-scale clinical trials. In cases where metabolite safety is not supported through the parent compound toxicology program, approaches for the direct safety testing of metabolites with regard to general and reproductive toxicology, safety pharmacology, and genetic safety have been defined.

SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.

Inhaled adenosine A2A receptor agonists for the treatment of chronic obstructive pulmonary disease

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.

Metabolite Testing in Drug Development

A significant consideration during the development of drug candidates is the impact of metabolites on efficacy and safety. Following the publication of the Metabolites in Safety Testing (MIST) guidance by the FDA in 2008, the focus on defining appropriate strategies to underwrite metabolite safety has intensified. Many analytical technologies are available to determine the identity and abundance of metabolites and further approaches continue to emerge. Furthermore, the scientific debate in recent years has enabled a pragmatic case-by-case approach to understand the significance of the metabolic pathways of novel compounds. In this respect, a number of key considerations apply, notably the specific structure, pharmacological activity, abundance, pharmacokinetics and physicochemical properties of individual metabolites, together with the administered dose of the parent compound. By considering all these factors, appropriate strategies can be defined to derive fit-for-purpose data to ensure that the safety and efficacy profiles of candidate compounds are properly understood.

The Design and Synthesis of a Novel, Orally Active, Selective ETA Antagonist

The potency and pharmacokinetic properties of an indole-based series of endothelin antagonists have been optimised using in vitro, in silico and in vivo methods. Compound 8 is oxidised in vivo to the active metabolite 7 and has been highlighted as an orally active agent suitable for further profiling. A synthesis of the active enantiomer of the lead compound (8a) and its metabolite (7a) has been developed and the pharmacokinetic and pharmacological profiles of 8a are presented.