Vascular Origin of Vildagliptin-induced Skin Effects in Cynomolgus Monkeys

Abstract

The purpose of this article is to characterize skin lesions in cynomolgus monkeys following vildagliptin (dipeptidyl peptidase-4 inhibitor) treatment. Oral vildagliptin administration caused dose-dependent and reversible blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and sores involving the extremities at ≥5 mg/kg/day and necrosis of the tail and the pinnae at ≥80 mg/kg/day after 3 weeks of treatment. At the affected sites, the media and the endothelium of dermal arterioles showed hypertrophy/hyperplasia. Skin lesion formation was prevented by elevating ambient temperature. Vildagliptin treatment also produced an increase in blood pressure and heart rate likely via increased sympathetic tone. Following treatment with vildagliptin at 80 mg/kg/day, the recovery time after lowering the temperature in the feet of monkeys and inducing cold stress was prolonged. Ex vivo investigations showed that small digital arteries from skin biopsies of vildagliptin-treated monkeys exhibited an increase in neuropeptide Y-induced vasoconstriction. This finding correlated with a specific increase in NPY and in NPY1 receptors observed in the skin of vildagliptin-treated monkeys. Present data provide evidence that skin effects in monkeys are of vascular origin and that the effects on the NPY system in combination with increased peripheral sympathetic tone play an important pathomechanistic role in the pathogenesis of cutaneous toxicity.

Clinical Safety and Tolerability of Vildagliptin – Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance

“…Skin lesions in extremities of Cynomolgus monkeys were observed with vildagliptin during early pre-clinical studies at doses of ≥5 mg/kg/day. 4 The lesions were of vascular origin and were not observed in any other animal species. 4 Similarly, the vildagliptin pooled safety analysis did not find an increased incidence of all skin-related AEs with vildagliptin compared to comparators (1.6 versus 1.4/100 SYEs, respectively); however, data from the recently published signal detection studies using pharmacovigilance databases showed increased reports of bullous pemphigoid (BP) in patients using DPP-4 inhibitors.…”

“… 4 The lesions were of vascular origin and were not observed in any other animal species. 4 Similarly, the vildagliptin pooled safety analysis did not find an increased incidence of all skin-related AEs with vildagliptin compared to comparators (1.6 versus 1.4/100 SYEs, respectively); however, data from the recently published signal detection studies using pharmacovigilance databases showed increased reports of bullous pemphigoid (BP) in patients using DPP-4 inhibitors. 58 , 59 The majority of bullous skin lesions were observed in elderly patients, 60 which is consistent with the epidemiology data suggesting increasing age as a risk factor for BP 61 – 63 In accordance with the guidance on routine care, monitoring for skin lesions in patients with T2DM treated with a DPP-4 inhibitor is recommended.…”

“…The in vitro and pre-clinical safety profiles were encouraging, with only a few species-specific safety signals pertaining to the gastrointestinal, cardiovascular (CV) and immune systems at concentrations that were approximately five to seven times the anticipated human exposure. 4 , 5 These insights from the pre-clinical studies were taken into account while designing the clinical development programme, and a special feature was the prospective, independent adjudication of CV events enabling a proper meta-analysis to establish the CV safety of vildagliptin at programme completion.…”

The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

“…These lesions were mediated by endothelial and medial hypertrophy/hyperplasia of arterioles at various levels of the dermis. These pathologic changes were related to increased NPY-Y 1 receptor signaling [33]. In humans, Boschmann et al showed that vildagliptin administration increased plasma norepinephrine (NE) concentrations in response to meals without causing a change in epinephrine levels [38].…”

Automated video-based heart rate tracking for the anesthetized and behaving monkey

“…In young infants or animals, placing the captor or maintaining it all throughout the experiment may turn out to be challenging if not impossible. In monkeys, recording HR either involves ECG or PPG under sedation [18][19][20] or implanting a telemetry device for HR measure during behaviour 21,22 . PPG recording or HR measures using captors embedded in a wearable jacket is also an option 11,23,24 .…”