Pharmacodynamic studies of nasal tetracosactide with salivary glucocorticoids for a noninvasive 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 5 studies: 4 open-label, sequence-randomized, crossover, pharmacodynamic studies testing 6 doses/formulations and a repeatability study. Additionally, pharmacokinetic analysis was undertaken using our chosen formulation, 500 µg tetracosactide with mucoadhesive chitosan, Nasacthin003, in our pediatric study. SETTING: Adult and children's clinical research facilities. PARTICIPANTS: A total of 36 healthy adult males and 24 healthy children. INTERVENTION: We administered all 6 nasal formulations using an European regulator endorsed atomization device. The IV comparators were 250 µg or 1 µg SST. MAIN OUTCOME MEASURES: We analyzed 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 IV Synacthen (P = 0.17). The repeatability coefficient at 60 minutes was 105 nmol/L for IV Synacthen and 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 IV SST and, with measurement at 60 minutes of salivary cortisol or cortisone, provides a noninvasive test for adrenal insufficiency.

Use of salivary cortisol and cortisone in the high- and low-dose synacthen test.

CONTEXT: Salivary cortisone reflects serum cortisol levels, is more sensitive than salivary cortisol at lower values of serum cortisol and is noninvasive. OBJECTIVE: To investigate the relationship between serum cortisol and salivary cortisol and cortisone following low- and high-dose synacthen. DESIGN AND SETTING: Prospective pharmacodynamic studies in clinical research facilities. PARTICIPANTS AND INTERVENTION: Thirty-five dexamethasone-suppressed, healthy adult males underwent an intravenous synacthen test: N = 23 low-dose (1 mcg), N = 12 high-dose (250 mcg). Paired serum and salivary samples were taken at 15 sampling points over 120 minutes. MAIN OUTCOME MEASURE: Serum cortisol and salivary cortisol and cortisone were analysed for correlations and by a mixed-effects model. RESULTS: At baseline, the correlation between serum cortisol and salivary cortisol was weak with many samples undetectable (r = .45, NS), but there was a strong correlation with salivary cortisone (r = .94, P < .001). Up to 50 minutes following synacthen, the correlation coefficient between serum cortisol and salivary cortisol and cortisone was <0.8, but both had a stronger correlation at 60 minutes (salivary cortisol r = .89, P < .001, salivary cortisone r = .85, P < .001). The relationship was examined excluding samples in the dynamic phase (baseline to 60 minutes). Salivary cortisol and cortisone showed a close relationship to serum cortisol. Salivary cortisone showed the stronger correlation: salivary cortisol r = .82, P < .001, salivary cortisone r = .96, P < .001. CONCLUSION: Following synacthen, both salivary cortisol and cortisone reflect serum cortisol levels, but there is a lag in their rise up to 60 minutes. The results support further research for possible future use of a 60-minute salivary cortisone measurement during the synacthen test.