Safety Assessment of 4′-Thio-β-d-Arabinofuranosylcytosine in the Beagle Dog Suggests a Drug-Induced Centrally Mediated Effect on the Hypothalamic-Pituitary-Adrenal Axis

Abstract

4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.

Adrenocortical hypertrophy: establishing cause and toxicological significance

“…As glucocorticoid function is dependent on carrier globulins in blood (CBG), these can also potentially affect glucocorticoid feedback mechanisms, which are essential for correct adrenocortical control and HPA function. Drugs and chemicals are also known to affect CRH, ACTH and central nervous system function, impinging on neuroendocrine control mechanisms (reviewed in Harvey et al ., 2008a; Harvey, 2010 and see Colagiovanni et al ., 2006; Colagiovanni and Meyer, 2008; Kumari et al ., 1997; Philip et al ., 1999; Tringali et al ., 2004).…”

“…As previously mentioned, stress is endocrinologically characterized by increased ACTH and increased glucocorticoid (Buckingham, 2008) where the increase in glucocorticoid is one of the most important physiological responses post infection or injury (Munck et al ., 1984) serving to quench otherwise overwhelming inflammatory responses. If increased ACTH and glucocorticoids are seen in the blood, a stress aetiology can be considered, but it is important to recognize that certain drugs can increase ACTH secretion via molecular pharmacological mechanisms (Hadley et al ., 1990; Kumari et al ., 1997) at the level of the hypothalamus or centrally (Colagiovanni et al ., 2006; Colagiovanni and Meyer, 2008; Kumari et al ., 1997; Philip et al ., 1999; Tringali et al ., 2004). The critical point, however, is the evidence of adrenocortical competence.…”

A Phase I Study of a New Nucleoside Analogue, OSI-7836, Using Two Administration Schedules in Patients with Advanced Solid Malignancies

“…The mechanism of this is unclear. An in-depth preclinical exploration of the potential mechanism of the observed fatigue was done at OSI Pharmaceuticals (22). First, at 10 Amol/L OSI-7836, there was no inhibition of a battery of receptors thought to be associated with fatigue, including adenosine; T4; adrenocorticorticotropic hormone; dopamine; g-aminobutyric acid; neuropeptides Y1 and Y2; serotonin; histamine receptors 1, 2, and 3; dopamine; and norepinephrine transporters.…”