Pragmatic Approaches to Determine the Exposures of Drug Metabolites in Preclinical and Clinical Subjects in the MIST Evaluation of the Clinical Development Phase

Abstract

The recent stream of regulatory guidelines on the Safety Testing of Drug Metabolites by the FDA in 2008 and the ICH in 2009 and 2012 has cast light on the importance of qualifying metabolite exposure as part of the safety evaluation of new drugs and has provided a much needed framework for the drug safety researcher. Since then, numerous publications interpreting the practicalities of the guidelines have appeared in the literature focusing on strategic approaches and/or adaptation of modern analytical methodologies, e.g., NMR and AMS, for the identification and quantification of metabolites in the species used in preclinical safety assessments and in humans. Surprisingly, there are few literature accounts demonstrating how, in practice, a particular strategy or analytical method has been used to qualify drug metabolites during the safety evaluation of a drug during clinical development. At the same time as the initial FDA and ICH guideline releases, the neuroscience therapy area of AstraZeneca had a number of projects in clinical development, or approaching this phase, which gave the authors a scaffold upon which to build knowledge regarding the safety testing of drug metabolites. In this article, we present how the MIST strategy was developed to meet the guidelines. Pragmatic approaches have evolved from the experience learned in various projects in DMPK at AstraZeneca, Södertälje, Sweden. Our experience dictates that there is no single strategy for qualifying the safety of drug metabolites in humans; however, all activities should be tied to two unifying themes: first that the exposure to drug metabolites should be compared between species at repeated administration using the relative method or a similar one; and second that the internal regulatory documentation of the metabolite qualification should be agnostic to external criteria (guidelines), indication, dose given, and timing.

Conversions of Tricyclic Antidepressants and Antipsychotics with Selected P450s fromSorangium cellulosumSo ce56

“…Drug metabolites formed at greater than 10% of the parent drug systemic exposure at steady state (FDA, 2008) or total drug-related exposure (European Medicines Agency, 2009) need to be tested in toxicological studies, whereby the International Conference on Harmonization guidelines take precedence over the FDA guidelines (Frederick and Obach, 2010;Haglund et al, 2014). For such studies, small (mg) to large quantities (in a gram scale) of these drug metabolites are necessary to provide standards for analytical and toxicological studies, respectively.…”

“…Any human metabolite representing .10% of the parent drug exposure at steady state has to be tested in safety studies (FDA, 2008). However, this FDA guidance is superseded by the guidelines of the International Conference on Harmonization (Frederick and Obach, 2010;Haglund et al, 2014). Concerning these guidelines, further safety testing is recommended for human metabolites that are observed at exposures .10% of total drug-related exposure and at significantly greater levels in humans than the maximum exposure seen in toxicity studies (European Medicines Agency, 2009).…”

Metabolites in Safety Testing Assessment in Early Clinical Development: A Case Study with a Glucokinase Activator

“…an assessment of circulating metabolite exposure across species at steady state to underwrite safety is a critical component of this stage (Luffer-Atlas, 2008;Leclercq et al, 2009;Yu et al, 2010;Nedderman et al, 2011;Haglund et al, 2014;Holmberg et al, 2014). The availability of steady-state plasma samples from the 14-day study on PF-04937319 in T2DM patients was an appropriate starting point toward MIST studies.…”

The debate on animal ADME studies in drug development: an update

“…A very recent paper describes practical applications of the MIST strategy adopted in AstraZeneca [26]: they stress that each project is to be dealt with on a case by case basis.…”