Pharmacokinetic evidence for hydrococortisone under and over replacement in adrenal insufficiency
Frederic Castinetti1, Nicolas Simon2, Floriane Ouliac1,3, Nathalie Lesavre4, Thierry Brue1 & Charles Oliver1
Aim and methods: Cortisol substitution in adrenal insufficiency (AI) is a matter of debate. We performed a pharmacokinetic analysis of plasma and salivary cortisol following oral hydrocortisone intake in patients with AI, and a pharmacokinetic modelling simulation. Fifty patients with primary (n=20) or secondary (n=30) AI were recruited. After 24-h plasma and salivary cortisol measurements under usual hydrocortisone treatment, a pharmacokinetic modelling with different simulated hydrocortisone dosing at different times of the day was performed.
Results: Thirteen different treatments regimens were observed: plasma and salivary cortisol levels were not in the normal range in the majority of patients. Pharmacokinetic modelling showed that there was a wide variability in cortisol concentrations whatever the scheme simulated, with the majority of patients under or over-replaced: the regimen with the higher proportion of simulated patients within the biological targets was 10+5+5 mg at 0730 h, 1200 and 1630 h respectively; however, even with this scheme, about 40% of patients would remain over or under-replaced.
Conclusions: Most patients are imperfectly treated. Our pharmacokinetic modelling showed that optimal substitution remains difficult with current tablets of hydrocortisone, whatever dose and time of administration used.