Myocardial necrosis related to hydrochlorothiazideinduced hypokalemia in cynomolgus monkeys

Abstract

-Myocardial necrosis is a serious adverse effect that results from the administration of some medications; therefore, when it is observed during preclinical studies it becomes a major drug development concern. Although data from preclinical monkey studies are generally extrapolated to predict effects in humans, few reports have described any mechanism that might explain the occurrence of myocardial necrosis. For this reason, we examined the association between hypokalemia and myocardial necrosis in monkeys. Four female cynomolgus monkeys (Macaca fascicularis) were treated with 50 mg/kg/day hydrochlorothiazide (a thiazide diuretic used for antihypertensive therapy) for 1 or 2 weeks. Clinical, hematological, plasma biochemical, and pathological examinations were conducted. Two animals were kept in a hypokalemic state from day 3 of dosing on, and their mean plasma potassium levels were 2.52 ± 0.24 and 2.60 ± 0.24 mmol/l. These animals were necropsied after 1 week of dosing due of the animals were occasionally hypokalemic, with mean plasma potassium levels of 3.13 ± 0.31 or 2.96 ± 0.30 mmol/l. These animals were necropsied after 2 weeks of dosing. One animal showed evidence of -gest that the severe hypokalemia induced by hydrochlorothiazide is likely to be associated with myocardial necrosis in monkeys.

Assessment of Cardiac Troponin I Responses in Nonhuman Primates during Restraint, Blood Collection, and Dosing in Preclinical Safety Studies

“…In 2012, cTnI was qualified by the FDA as a marker of cardiac necrosis in rats and dogs for use in preclinical studies (Woodcock 2012). At the time the qualification document was submitted in late 2008, there were limited published studies demonstrating the use of this biomarker in nonhuman primates (NHP) studies, although more recently, additional publications have become available (Dunn et al 2012;Minomo et al 2009;Schultze et al 2015;Takeuchi et al 2008;Zabka, Irwin, and Albassam 2009). Based on the paucity of published information on the use of this biomarker in NHP at the time of submission, cTnI was not officially qualified for use in NHP.…”