E. Charmandari et al., Bioavailability of oral hydrocortisone in patients with congenital adrenalhyperplasia due to 21-hydroxylase deficiency, J ENDOCR, 169(1), 2001, pp. 65-70
The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP
21) deficiency requires glucocorticoid substitution with oral hydrocortison
e given twice or thrice daily. In paediatric practice little is known of th
e bioavailability of oral hydrocortisone tablets used in these patients. Th
e aim of this study was to assess the bioavailability of oral hydrocortison
e and to evaluate current replacement therapy in the light of cortisol phar
maco-kinetic properties.
We determined the bioavailability of hydrocortisone following oral and intr
avenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4
years) adequately controlled CYP21 deficient patients. Serum total cortisol
concentrations were measured at 20-min intervals for 24 h while patients w
ere on oral substitution therapy, and at 10-min intervals for 6 h following
an intravenous bolus of hydrocortisone ill a dose of 15 mg/m(2) body surfa
ce area. Thr area under the serum total cortisol concentration versus time
curve (AUC) following oral and intravenous administration of hydrocortisone
was calculated using the trapezoid method. The bioavailability was estimat
ed by dividing thr corrected for dose AUC after oral hydrocortisone adminis
tration by che corrected for dose AUC after the intravenous hydrocortisone
administration and was exemplified as a percentage. After oral administrati
on of hydrocortisone ill the morning, median serum total cortisol concentra
tions reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2h (rang
e: 0.3-3.3h) and declined monoexponentially thereafter to reach undetectabl
e concentrations 7 h (range: 5-12h) after administration. Following adminis
tration of the evening hydrocortisone dose, median peak cortisol concentrat
ion of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range
: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable con
centrations at 9 h (5-12 h) after administration of the oral dose. After th
e intravenous hydrocortisone bolus a median peak serum total cortisol conce
ntration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (r
ange: 10-20 min). Serum cortisol concentrations fell rapidly and reached un
detectable levels 6 h after the hydrocortisone bolus. The absolute bioavail
ability of oral hydrocortisone in the morning was 94.2% (90% confidence int
erval (CI): 82.8-105.5%) whereas the apparent bioavailability ill the eveni
ng was estimated to be 128.0% (90% CI: 119.0-138.0%).
We conclude that the bioavailability of oral hydrocortisone is high and may
result in supraphysiological cortisol concentrations within 1-2 h after ad
ministration of high doses. The even higher bioavailability in the evening,
estimated using as reference the data derived from the intravenous adminis
tration of hydrocortisone bolus in the morning, is likely to reflect a decr
ease in the hydrocortisone clearance in the evening. Decisions on the sched
ule and frequency of administration in patients with congenital adrenal hyp
erplasia should be based on the knowledge of the bioavailability and other
pharmacokinetic parameters of the hydrocortisone formulations currently ava
ilable.