medwireNews: Giving hydrocortisone four times daily (QID) at a time-varying dose may be the best approach for children with congenital adrenal hyperplasia (CAH), say the authors of a pharmaco (P)-kinetic and P-dynamic modelling study.
This strategy, giving 38% of the daily dose at 06:00, 22% at 12:00, 17% at 18:00 and 22% at 00:00, has three clear advantages, say Charlotte Kloft (Freie Universitaet Berlin, Germany) and co-researchers.
First, their modelling showed that it would minimise the time patients spent with too low plasma cortisol concentrations, defined as less than 50 nmol/L. This was based on the finding that a cortisol plasma level of 48.6 nmol/L produced 50% inhibition of the production of 17-hydroxyprogesterone (17-OHP) – a cortisol precursor that is elevated in patients with CAH.
Second, this QID dosing produced a cortisol plasma profile closest to the physiological profile seen in healthy children.
Third, the dosing regimen resulted in an increased proportion of children having serum cortisol within the target range of 50–500 nmol/L, with 75% of prepubertal patients being within this range at least 75% of the time (depending on the dose), compared with around 60% of the time with thrice-daily dosing. The corresponding values for pubertal patients were approximately 80% versus 60%.
Thrice-daily dosing is currently recommended due to the short half-life of cortisol, say the researchers.
“Use of such a treatment regimen, however, results in several peaks with supraphysiological cortisol concentrations followed by prolonged periods with hypocortisolaemia”, they write in The Journal of Clinical Endocrinology & Metabolism.
Their preferred QID schedule is based on a pharmacokinetic model describing the absorption, distribution, metabolism and excretion of hydrocortisone, and a pharmacodynamic model describing its effects, based on its ability to inhibit the production of 17-OHP.
The team created these models from cortisol and 17-OHP values measured in 30 children with salt-wasting CAH every 20 minutes for up to 24 hours after oral hydrocortisone administration and every 10 minutes for up to 6 hours after intravenous administration. Seventeen children were given twice-daily oral hydrocortisone and 13 were given thrice-daily doses, and 16 were also given an intravenous dose on a separate day. The children were aged from 7 to 17 years; nine were prepubertal.
The patients’ baseline pre-dose cortisol and 17-OHP levels varied widely, from undetectable to 516 and 1490 nmol/L, respectively. The researchers suggest this could be partly explained by residual endogenous cortisol production, and say that accounting for this baseline variability improved the accuracy of their models.
Of note, 17-OHP profiles were largely unaffected by changes in hydrocortisone dosing schedules, despite the impact on cortisol profiles, with 75% of patients being within the target range a maximum of only 50% of the time, regardless of the dosing regimen.
This suggests “that 17-OHP alone is not a suitable marker for monitoring of cortisol replacement therapy”, say Kloft and team.
The researchers say that a prospective trial is needed to test their QID schedule in CAH patients, “to confirm if there is a clinical benefit for the patients with respect to improvement in disease status, growth velocity, and lower androgen concentrations” and also to assess practical issues such as adherence.
But they add that modified-release hydrocortisone formulations, or even continuous subcutaneous infusion, could provide workable alternative approaches.
By Eleanor McDermid
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J Clin Endocrinol Metab 2020; doi:10.1210/clinem/dgaa071