Effect of Dose Size on the Pharmacokinetics of Oral Hydrocortisone Suspension

Roger, D.; Craig, William A.; Welling, Peter G.

doi:10.1002/jps.2600711029

Cited by 29 publications

(6 citation statements)

References 8 publications

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“…Our study showed that PK exposure parameters for DR-HC were less than dose proportional in the fasted state, which confirms previous findings for DR-HC ( 15 ) and is in line with PK data for immediate-release and suspension formulations of hydrocortisone in the same dose range ( 36 , 37 ). This important PK property of oral hydrocortisone makes it difficult to determine the optimal dosing regimen during intercurrent illness in AI, for which current management is inadequate ( 1 , 7 , 9 , 38 ).…”

Section: Discussionsupporting

confidence: 92%

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

Johannsson

Lennernäs

Marelli³

et al. 2016

European Journal of Endocrinology

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ObjectiveOral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure−time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5–20mg and assess intrasubject variability.MethodsThirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20−55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography−tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration−time profiles.ResultsDR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0−4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration−time curve (AUC)0−∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences.ConclusionsDR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional – an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

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Section: Discussionsupporting

confidence: 92%

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

Johannsson

Lennernäs

Marelli³

et al. 2016

European Journal of Endocrinology

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“…One caveat of the above studies is that the total exposure of cortisol is higher when the same daily dose of hydrocortisone is administered divided into three or four daily doses than at BID administration. This is due to the fact that increasing the dose of hydrocortisone at one dose occasion does not result in a proportional increase in total exposure of cortisol due to the non-linear bioavailability of orally administered hydrocortisone [26]. Thus, there might be a short-term perceived benefit of the increased cortisol exposure whereas the long-term risk may increase.…”

Section: Discussionmentioning

confidence: 99%

Current practice of glucocorticoid replacement therapy and patient-perceived health outcomes in adrenal insufficiency - a worldwide patient survey

et al. 2012

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BackgroundThe aim was to survey current practice in glucocorticoid replacement therapy and self-perceived health outcomes in patients with adrenal insufficiency.MethodsParticipants were recruited via patient organizations to respond anonymously to a web-based survey developed by clinical experts. Unique entries were set up for each patient organization enabling geographical localization of the entries.Results1245 participants responded (primary adrenal insufficiency: 84%; secondary adrenal insufficiency: 11%; unsure: 5%). Therapies included hydrocortisone (75%), prednisone/prednisolone (11%), cortisone acetate (6%) and dexamethasone (4%). Dosing regimens were once daily (10%), twice daily (42%), thrice daily (32%) or other (17%). Compromised subjective health necessitating changes to physical activity or social-, work- or family life was reported by 64% of the participants. 40% of the participants reported absence from work/school in the last 3 months. Irrespective of diagnosis, 76% were concerned about long-term side-effects of therapy, mainly osteoporosis (78%), obesity (64%) and cardiovascular morbidity (46%). 38% of the participants had been hospitalized in the last year.ConclusionsGlucocorticoid replacement therapy among the respondents consisted primarily of hydrocortisone administered twice or thrice daily. A majority reported impact of their disease or treatment on subjective health requiring alterations in e.g. physical activity or family life. Three quarters reported concerns about long-term side-effects of the treatment. These data demonstrate - from the patients' perspective - a need for improvement in the management of adrenal insufficiency.

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“…The patients receiving conventional hydrocortisone therapy doubled the dose at each appointed administration time, and patients receiving DR-HC received a second DR-HC dose 8±2 h after the first dose. The reason for adopting this regimen for DR-HC is that the relationship between cortisol exposure and dose is not proportional (19). Thus, if a single dose is increased from 20 to 40 mg, the serum cortisol exposure is not doubled, whereas the same dose of hydrocortisone administered on two separate occasions will double the exposure.…”

Section: Methodsmentioning

confidence: 99%

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

Nilsson

Marelli²,

Fitts

et al. 2014

European Journal of Endocrinology

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ObjectiveThe objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).DesignRandomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.MethodsSixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).ResultsIn stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.ConclusionsThis long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

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Effect of Dose Size on the Pharmacokinetics of Oral Hydrocortisone Suspension

Cited by 29 publications

References 8 publications

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

Current practice of glucocorticoid replacement therapy and patient-perceived health outcomes in adrenal insufficiency - a worldwide patient survey

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

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