Systemic Exposure to the Metabolites of Lesogaberan in Humans and Animals: A Case Study of Metabolites in Safety Testing

Abstract

During preclinical and early phase clinical studies of drug candidates, exposure to metabolites should be monitored to determine whether safety conclusions drawn from studies in animals can be extrapolated to humans. Metabolites accounting for more than 10% of total exposure to drug-related material (DRM) in humans are of regulatory concern, and for any such metabolites, adequate exposure should be demonstrated in animals before large-scale phase 3 clinical trials are conducted. We have previously identified six metabolites, M1-M6, of the gastroesophageal reflux inhibitor lesogaberan. In this study, we measured exposure in humans, rats, and beagle dogs to lesogaberan and these metabolites. Plasma samples were taken at various time points after lesogaberan dosing in two clinical and three preclinical studies. Concentrations of lesogaberan and its metabolites were measured, and exposures during a single dosing interval were calculated. The parent compound and metabolites M1, M2, M4, and M5 were together shown to constitute all significant exposure to DRM in humans. Only M4 and M5 were present at levels of regulatory concern (10.6% and 18.9% of total exposure to DRM, respectively, at steady state). Absolute exposure to M5 was greater in rats during toxicology studies than the highest absolute exposure observed in humans at steady state (117.0 mmol 3 h/liter vs. 52.2 mmol 3 h/liter). In contrast, exposure to M4 in rats was less than 50% of the highest absolute exposure observed in humans. Further safety testing of this metabolite may therefore be required.

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 Importance of the Human Mass Balance Study in Regulatory Submissions

“…Literature example of metabolites (M1, M2, M4, M5) slowly eliminated in plasma. Lesogaberan and metabolite concentrations plotted against time after the final lesogaberan dose in humans, single 100‐mg dose ( 14 C‐labeled) …”

“…In some cases, the total recovery of radioactivity in urine and feces was < 90% of the dose, and < 80% of the recovered radioactivity was identified. This may be a result of the persistent metabolites ( Figure ) or metabolites with very long half‐life . In at least one example (ibrutinib (Imbruvica)), the elimination of covalently bound radioactivity was very slow.…”

“…In most cases, this was the result of an incomplete profiling of the complete radioactivity time course profile, and in some cases, plasma was only profiled during the first 24 hours or less, whereas the radioactive half‐life was much longer, e.g., lurasidone (Latuda). In a number of cases, a longer plasma half‐life of radioactivity than for the parent compound was evident, e.g., opicapone (Ongentys) and ponatinib (Iclusig), indicating metabolites with slower elimination rate limited clearance (see Figure for a literature example). In one case, uncertainties about levels of metabolites in later time points meant a concern over possible unidentified persistent major metabolites, e.g., opicapone (Ongentys).…”

Simulation of human plasma concentration–time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling

“…Food and Drug Administration, 2008) have recommended that drug metabolites whose circulating concentrations in humans exceed 10% of the total drug-related material need to be qualified in preclinical toxicology species for systemic coverage. A pragmatic first step in underwriting safety concerns due to MIST involves comparison of steadystate circulating metabolite(s) exposure across preclinical species and humans followed by additional scrutiny in cases where metabolites are formed in disproportionately higher quantities or exclusively produced in humans (Holmberg et al, 2014;Leclercq et al, 2009;Minagawa et al, 2012;Nedderman, 2009;Zhu et al, 2009).…”