Variability in Hydrocortisone Pharmacokinetics Following Intravenous and Oral Administration in Patients with Adrenal Insufficiency
MC Devers1, AH Thomson4, M Freel2, D Grant2, K Campbell2, M Wallace3 & JMC Connell2
Hydrocortisone is the standard replacement therapy in patients with primary or secondary adrenal insufficiency (AI) but there is no current consensus on the most appropriate replacement dose and the extent to which this varies between individuals. This study examines inter-individual variability in cortisol metabolism in patients taking hydrocortisone therapy and investigates the relationship between plasma and salivary concentrations.
Subjects and Methods
Twenty-six patients aged 34-65 years (median 47) participated, 10 (3 male) with primary AI, 16 (8 male) with secondary AI. Salivary and plasma cortisol levels were measured following intravenous (20 mg bolus) and oral administration (10, 15 or 20 mg, 24 subjects) of hydrocortisone. Local Ethics Committee approval was obtained.
After intravenous administration, plasma cortisol concentrations declined mono- exponentially in 7 and bi-exponentially in 19 patients. Cmax ranged from 715-8313 nmol/L (median 1253) and elimination half-life (t1/2) from 1.1-6.1 hours (median 2.2). AUC ranged from 1112-12259 nmol.h/L (median 2726). Maximum salivary concentrations of 46-1810 nmol/L (median 168) were observed 0.2 to 3.6 hours after the IV dose and the median t1/2 was 1.5 hours (range 0.6-3.6).
After oral administration, wide variability in plasma and salivary cortisol profiles was observed. Plasma Cmax ranged from 422-1554 nmol/L (median 795) and salivary from 21-2000 nmol/L (median 144). Tmax ranged from 0.25-2 hours for both plasma and saliva. Elimination t1/2 could only be estimated in 18 subjects and had medians of 1.9 hours (plasma) and 1.5 hours (saliva). The median (range) plasma AUC (corrected for 20 mg) was 3342 (885-7819) nmol.h/L and saliva AUC was 304 (94-901) nmol.h/L.
Wide inter-individual variability in plasma and salivary profiles of cortisol was identified following the administration of IV and oral hydrocortisone to patients with adrenal insufficiency. These results suggest that salivary cortisol measurements alone cannot be used for individual hydrocortisone dosage adjustment.