Pharmacodynamic studies of nasal tetracosactide with salivary glucocorticoids for a non-invasive Short Synacthen Test

Context: The Short Synacthen Test (SST) is the gold standard for diagnosing adrenal insufficiency. It requires invasive administration of Synacthen, venous sampling and is resource-intensive.

Objective: To develop a nasally administered SST, with salivary glucocorticoids measurement, to assess the adrenal response.

Design: We conducted five studies: four open-label, sequence-randomised, crossover, pharmacodynamic studies testing six doses/formulations and a repeatability study. Additionally, pharmacokinetic analysis was undertaken using our chosen formulation, 500 µg tetracosactide with mucoadhesive chitosan, Nasacthin003, in our paediatric study.

Setting: Adult and children’s Clinical Research Facilities.

Participants: 36 healthy adult males and 24 healthy children.

Intervention: We administered all six nasal formulations using a CE marked atomisation device. The intravenous comparators were 250 µg or 1 µg SST.

Main Outcome Measures: We analysed paired blood and saliva samples for plasma cortisol and salivary cortisol and cortisone.

Results: The addition of chitosan to tetracosactide and dose escalation increased peak cortisol response (p=0·01 and 0·001 respectively). The bioavailability of Nasacthin003 was 14·3%. There was no significant difference in plasma cortisol at 60 minutes between 500 µg Nasacthin003 and 250 µg intravenous Synacthen (p=0.17). The repeatability coefficient at 60 minutes was 105 nmol/l for intravenous Synacthen and for salivary cortisol and cortisone was 10·3 and 21·1 nmol/L respectively. The glucocorticoid response in children was indistinguishable from that of adults.

Conclusions: Nasal administration of Nasacthin003 generates equivalent plasma cortisol values to the 250 µg intravenous SST and, with measurement at 60 minutes of salivary cortisol or cortisone, provides a non-invasive test for adrenal insufficiency.