Characterization of the Inflammatory Response to a Highly Selective PDE4 Inhibitor in the Rat and the Identification of Biomarkers that Correlate with Toxicity

Abstract

The primary toxicity associated with repeated oral administration of the PDE4 inhibitor IC542 to the rat is an inflammatory response leading to tissue damage primarily in the gastrointestinal tract and mesentery. Although necrotizing vasculitis is frequently seen with other PDE4 inhibitors, blood vessel injury was rare following IC542 administration and was always associated with inflammation in the surrounding tissue. The incidence and severity of the histologic changes in these studies correlated with elevated peripheral blood leukocytes, serum IL-6, haptoglobin, and fibrinogen, and with decreased serum albumin. By monitoring haptoglobin, fibrinogen and serum albumin changes in IC542-treated rats, it was possible to identify rats with early histologic changes that were reversible. Since PDE4 inhibition is generally associated with anti-inflammatory activity, extensive inflammation in multiple tissues was unexpected with IC542. Co-administration of dexamethasone completely blocked IC542-induced clinical and histologic changes in the rat, confirming the toxicity resulted from inflammatory response. In addition, IC542 augmented release of the proinflammatory cytokine IL-6 in LPS-activated whole blood from rats but not monkeys or humans. The effect of IC542 on IL-6 release from rat leukocytes in vitro is consistent with the proinflammatory response observed in vivo and demonstrates species differences to PDE4 inhibition.

Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

“…For example, a recent study demonstrated that levels of PDE4 activity in many tissues are much higher in rats than in humans, which would explain why rats are more susceptible to PDE4 inhibitor-induced toxicities [119]. In addition, the PDE4 inhibitor IC 542 significantly enhances LPS-induced IL-6 release from rat whole blood [120], but has no potentiating effect on LPS-induced IL-6 release from human or non-human primate blood. The potential for developing vasculitis with systemically active PDE inhibitors does, however, require careful monitoring in humans, and there have been attempts to identify potential predictive biomarkers for this unwanted effect.…”

Selective Inhibition of PDE4 in Wistar Rats Can Lead to Dilatation in Testis, Efferent Ducts, and Epididymis and Subsequent Formation of Sperm Granulomas

“…Several target organs after administration of PDE4 inhibitors to rats have been described (Dietsch et al 2006;Larson et al 2006;Mecklenburg et al 2006;Peter et al 2011;Sheth et al 2011;Slim et al 2003;Zhang et al 2002Zhang et al , 2008, but to our knowledge no detailed reports about changes in male reproductive organs are available so far. Testicular dilatation and epididymal sperm granulomas were repeatedly seen in the 4-week toxicity studies with PDE4 inhibitors of different chemical classes at our facility.…”

“…In rats, the most frequently reported target site is the mesentery. Further target sites in rats are the heart, gastrointestinal tract, pancreas, liver, kidney, and the soft tissue of hind limbs (Dietsch et al 2006;Larson et al 1996;Mecklenburg et al 2006;Peter et al 2011;Sheth et al 2011;Slim et al 2003;Zhang et al 2002Zhang et al , 2008. Although differences exist in localization and degree of vascular injury, which might be related to different doses, potencies, or binding affinities (Wang et al 2007), lesions seem in general to be related to the pharmacodynamic action of PDE4 inibition in rats.…”

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

“…The histologic lesions of small molecule-related DIVI have been well described (Dietsch et al 2006;Hanton et al 2008;Joseph, Rees, and Dayan 1996;Joseph 2000;C. Louden and Morgan 2001;Weaver et al 2008;Yuhas et al 1985), and include perivascular edema, inflammatory cell infiltrates (frequently including macrophages and neutrophils), and mural or perivascular hemorrhage together with degenerative or necrotic changes of the tunica media.…”