Translational in-vitro in-vivo model to correlate HIPS derived cardiomyocyte contractility assay and in-vivo dog telemetry based dPdtmax measurements
(1) Raja Venkatasubramanian, (2) Teresa A. Collins, (1) Lawrence J. Lesko, (3) Jay T. Mettetal, (1) Mirjam N. Trame
(1) Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL; (2) Drug Safety and Metabolism, AstraZeneca, Cambridge, UK; (3) Drug Safety and Metabolism, AstraZeneca, Waltham, MA
Objectives: Cardiovascular safety is one of the most frequent causes of safety related attrition both pre-clinically and clinically. Limited progress has been made in the development of in-vitro in-vivo translation of drug induced cardiac contractility changes. The objective was to explore the translation of in-vitro cardiac contractility assay results obtained from human induced pluripotent stem cell derived cardiomyocytes (HIPS-CM) to drug induced changes in dPdtmax observed in-vivo, within dog telemetry studies.
Methods: Pharmacological in-vitro alteration of calcium transients in HIPS-CM from compounds at various stages during drug discovery/development within AstraZeneca were available. Additionally, in-vivo cardiac contractility biomarker data, dPdtmax, from in-house AstraZeneca pre-clinical dog telemetry studies were utilized. Plasma drug concentration measurements or predictions from a developed dog PK model were used as exposure data. Drug induced changes in dPdtmax were calculated by correcting for baseline/placebo effects and for day-to-day variations in baseline [1]. A 26% change in dPdtmax, currently used as the effect size to appropriately power dog telemetry studies in AstraZeneca, was considered as a significant pharmacodynamic threshold to identify potent in-vivo drug concentrations using LOESS approximation. Geometric mean of concentrations across different compounds was used as the average drug concentration threshold at which in-vivo effects of dPdtmax leading to safety risks can be expected.
Results: Data from n=6 compounds out of all data provided from in-house AstraZeneca studies were identified to have PK, dPdtmax and EC50 information and used during this analysis. Unbound plasma concentration (Cunbound) normalized by the potency (EC50) was used as the appropriate PK parameter. Potency normalized concentrations of 0.10 [95%CI 0.0014-7.65] mM/mM was determined as the potent exposure that would result in a 26% drug induced change in dPdtmax. Potency normalized plasma concentration was found to be sensitive to the threshold for dPdtmax change across all 6 compounds.
Conclusions: A translational in vitro in vivo approach was successfully developed and adequate correlation was observed between drug induced changes in dPdtmax in dogs and the corresponding in-vitro potency normalized unbound plasma levels. This was used to determine the potent exposure at which significant changes in in-vivo dPdtmax, a key cardiac safety concern, can be observed.
References:
[1] Pointon, Amy, et al. "Assessment of cardiomyocyte contraction in human-induced pluripotent stem cell-derived cardiomyocytes." Toxicological Sciences 144.2 (2015): 227-237.