Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial

Buning, Jorien Werumeus; Touw, Daan; Brummelman, Pauline; Dullaart, Robin; Berg, Gerrit van den; Kamp, Jasper; Wolffenbuttel, Bruce H. R.; Beek, André P van

doi:10.1016/j.metabol.2017.02.005

Cited by 32 publications

(17 citation statements)

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“…While some patients displayed differences in 17OHP and A4 concentrations when treated with the different treatment regimens, other patients did not. This variability may be due to large interindividual differences in pharmacokinetic parameters ( 32-34 ), as subgroup analysis (interaction between treatment and eg, treatment dose per meters squared, tanner staging, or sex) could not explain this variability. For patients with higher clearance of HC, a relatively higher dose (either morning or evening) may, in contrast to patients with lower clearance, not result in lower levels of 17OHP and A4 6 or 8 hours after HC administration.…”

Section: Discussionmentioning

confidence: 99%

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency

Schröder

Herwaarden

Span

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice-daily, but there is debate about the optimal timing of highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). Objective We aimed to compare two standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure, sleep and activity scores. Design and setting Six-week cross-over study. Patients Thirty-nine patients (4-19 years) with 21OHD. Interventions Patients were treated for three weeks with highest hydrocortisone dose in the morning, followed by three weeks with highest dose in the evening (n=21), or vice-versa (n=18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5.00am; 7.00am; 3.00pm; and 11.00pm during the last two days of each treatment period. Main outcome measure Comparison of saliva 17OHP and A4 levels between two treatment strategies. Results Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5.00am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The two treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal blood pressure, and activity- and sleep scores. Conclusion No clear benefit for either treatment schedule was established. Given the variation in individual responses we recommend to individually optimize dose distribution and monitoring disease control at multiple timepoints.

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Section: Discussionmentioning

confidence: 99%

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency

Schröder

Herwaarden

Span

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…In patients with secondary adrenal insufficiency, estimations of the individual pharmacokinetic parameters were calculated as described in detail elsewhere . In short, the Kinpop module of MwPharm version 3.81 was used to calculate a one‐compartment and two‐compartment population model for plasma total cortisol.…”

Section: Methodsmentioning

confidence: 99%

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Vulto

Bergthorsdottir

Faassen

et al. 2019

Clinical Endocrinology

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ObjectiveThis study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency.DesignTwenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies.Patients and measurementsPatients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC‐MS/MSResultsCompared to controls, progressively lower concentrations of the glucocorticoid precursors 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11‐deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24‐hour free cortisol excretion in urine.ConclusionsAdrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.

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“…Previously, we showed that half of the patients with secondary adrenal insufficiency (SAI) had detectable amounts of 11-deoxycortisol, a marker of residual adrenal cortisol production ( 17 ). In addition, slow and fast metabolizers were identified, with a 10-fold difference in plasma cortisol exposure between groups who received a similar weight adjusted hydrocortisone dose ( 18 ). However, because cortisol pharmacokinetics may not accurately reflect the effects of glucocorticoid receptor activation, it is of interest to investigate cortisol pharmacodynamics as well.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to Adrenal Crisis Is Associated With Differences in Cortisol Excretion in Patients With Secondary Adrenal Insufficiency

et al. 2022

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ObjectiveTo compare cortisol pharmacokinetics and pharmacodynamics mapped through several glucocorticoid sensitive pathways in patients on hydrocortisone substitution with or without an adrenal crisis.DesignA post-hoc analysis of a previously conducted randomized controlled trial in patients with secondary adrenal insufficiency examining the effects of 2 weight-adjusted hydrocortisone doses.MethodsComparisons were primarily made on a hydrocortisone dose of 0.2-0.3 mg/kg/day for plasma cortisol and cortisone, 24-hour urinary steroid profile, the glucocorticoid sensitive tryptophan-kynurenine pathway, the renin-angiotensin-aldosterone system and aspects of quality of life. Variables of interest were also analyzed on the hydrocortisone dose of 0.4-0.6 mg/kg/day.ResultsOut of 52 patients, 9 (17%) experienced at least one adrenal crisis (AC+ group) and 43 did not develop an adrenal crisis (AC- group) during an observation period of 10 years. 24-hour urinary excretion of cortisol and cortisone were lower in the AC+ group (0.05 [IQR 0.03; 0.05] vs. 0.09 [0.05; 0.12] µmol/24h, P=0.01and 0.13 [0.10; 0.23] vs. 0.24 [0.19; 0.38] µmol/24h, P=0.04, respectively). No differences in pharmacokinetics of cortisol were observed. Kynurenine concentrations were higher in the AC+ group (2.64 [2.43; 3.28] vs. 2.23 [1.82; 2.38] µmol/L, P=0.03) as was general fatigue (Z-scores 1.02 [-0.11; 1.42] vs. -0.16 [- 0.80; 0.28], P=0.04). On the higher hydrocortisone dose urinary excretion of cortisol and cortisone was still significantly lower between the AC- and AC + group. The differences in glucocorticoid sensitive variables disappeared.ConclusionPatients susceptible to an adrenal crisis demonstrated differences in cortisol and cortisone excretion as well as in pharmacodynamics when compared to patients who did not experience an adrenal crisis, suggesting a biological predisposition in certain patients for the development of an adrenal crisis.

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Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial

Cited by 32 publications

References 35 publications

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Susceptibility to Adrenal Crisis Is Associated With Differences in Cortisol Excretion in Patients With Secondary Adrenal Insufficiency

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