The Toxicity of SCH 351591, a Novel Phosphodiesterase-4 Inhibitor, in Cynomolgus Monkeys

Abstract

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low-and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

“…PDE 4 inhibitors have been shown to cause arteritis and vasculitis (inflammation of the arteries and vessels) in rats (Langle et al, 1994;Larson et al, 1996; http://www.fda.gov/ohrms/ dockets/ac/03/transcripts/3976T1.doc; Mecklenburg et al, 2006) and minipigs (Vogel et al, 1999). This finding was demonstrated more recently in cynomolgus monkeys, which was the first observation using this class of compounds in nonhuman primates (Losco et al, 2004). Recent data provided further evidence for inflammatory implications of PDE 4 inhibitors.…”

The Role of eNOS Phosphorylation in Causing Drug-induced Vascular Injury

“…However, preclinical safety evaluations have indicated that PDE-4i induce vascular lesions, primarily in the mesenteric arteries of rats and in the coronary arteries of dogs, pigs, and monkeys (Hanton et al 2008;Heaslip et al 1994;Losco et al 2004;Zhang et al 2008). It is not known whether similar effects would be observed in humans.…”

Scientific and Regulatory Policy Committee Points-to-consider Paper*

“…Depending on the drug and duration of exposure, a mixed perivascular inflammatory cellular response can be observed. Perivascular fibrosis with intimal and medial hypertrophy is noted chronically (Losco et al 2004). Fulminant lesions can be observed as soon as 12 hr (Zhang et al, 2002a), but more typically several days of dosing are required to induce the full spectrum of morphologic changes (Zhang et al 2008).…”

“…DIVI lesions associated with vasoactive compounds are very rare in the mouse but have been observed commonly in rats following treatment with phosphodiesterase (PDE) 3 and 4 inhibitors, adenosine receptor agonists, dopaminergic agonists, endothelin receptor antagonists, angiotensin, bradykinin, a-adrenergic agonists, and K ir channel antagonists (Herman et al 1989;Johansson 1981;W. Kerns et al 2005;Losco et al 2004;Mikaelian et al 2014).…”