Introduction: Worldwide the Short Synacthen Test (SST) is the most popular diagnostic investigation for adrenal insufficiency (AI) amongst both paediatric and adult endocrinologists. Cannulation and blood sampling are required making it invasive, time-consuming and resource-intensive. We have previously validated a reliably absorbed and well tolerated formulation of nasal synacthen (Nasacthin003) in healthy adult males, measuring the glucocorticoid response in salivary cortisol and cortisone. This paediatric study establishes a novel non-invasive SST in children.
Methods: A prospective, open-label, sequence-randomised, cross-over pharmacokinetic study of Nasacthin003 in 24 healthy children aged 414 years. Volunteers were dexamethasone suppressed to establish a uniform glucocorticoid baseline and enable measurement of plasma Synacthen. For the intravenous comparator participants received either 250 mcg (N=12) or 1 mcg (N=12) IV synacthen. Nasacthin003 was administered via a mucosal atomiser device, 0.1 ml to each nostril. During both three-hour visits 14-paired blood and saliva samples were taken (−15, −1, 2, 5, 10, 15, 20, 30, 40 50, 60, 75, 90 and 120 minutes) and measurements of plasma Synacthen (ACTH EIA), plasma cortisol (chemiluminescent immunoassay) and salivary cortisol and cortisone (LC-MS/MS) made. The paediatric data was compared to our previous healthy male adult cohorts.
Results: The Cmax, Tmax and time-concentration curves for this child cohort were essentially indistinguishable from the historic adult data for all glucocorticoid biomarkers in all three tests (250 mcg IV, 1 mcg IV and Nasacthin003). The mean plasma cortisol Cmax in children compared with adults was 568 nmol/l (±79) vs 558 (±110), 406 (±77) vs 400 (±89) and 630 (±54) vs 615 (±51) for Nasacthin003, 1 mcg IV and 250 mcg IV respectively. The median Tmax was 75 minutes (IQR 30 mins) in both children and adults following Nasacthin003, 30 mins for IV 1 mcg and 120 mins for IV 250 mcg. The administeration of Nasacthin003 in children resulted in a slightly higher exposure (synacthen AUC0-inf) compared to adults, due to smaller body size. Salivary cortisol and cortisone samples were closely correlated with their paired serum samples (r=0.88 and 0.90 respectively). Salivary cortisone was the more sensitive marker of adrenocortical response at lower plasma cortisol values compared to salivary cortisol.
Conclusions: We have developed a novel non-invasive SST, with PK parameters demonstrating that Nasacthin003 stimulation leads to an indistinguishable glucocorticoid response in both serum and saliva compared to high and low-dose IV synacthen.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology