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Hydrocortisone

Introduction

  • synthetic cortisol
    • cannot be bioanalytically separated from endogenous cortisol [๐Ÿ“–]
  • the relatively short half-life of 1.5 h
  • lack of licensed formulation for this population (for <6yo)
  • Dose
    • still growing children: 8 mg/m\(^2\)/day divided in 3-4 doses [๐Ÿ“–]
    • more specific: 10-15 mg/m\(^2\)/day divided into 3 doses [๐Ÿ“–]
    • recommended daily dose to adult patients with adrenal insufficiency [๐Ÿ“–]
      • at 06:00 10 mg
      • at 14:00 5 mg
      • at 22:00 5 mg
  • modified release formulations [๐Ÿ“–]
    • Plenadren
    • Chronocort
  • administration
    • subcutaneously via insulin -> circadian cortisol profile and improved 17-OHP concentrations [๐Ÿ“–]
  • BCS (biopharmaceutical classification system) class II [๐Ÿ“–]
    • low dissolution rate and high intestinal permeability [๐Ÿ“–]

Pharmacokinetics

Absorption

  • Parameters
    • passive diffusion and is a poor substrate for the efflux protein P-glycoprotein [๐Ÿ“–]
    • \(T_{max}\)
      • tablet 1-1.7 h
        • note: 1.7 h in high dose 50 mg [TBA]
      • solution 0.7-1 h
      • pediatric adrenal insufficiency 0.33-3 h
    • \(t_{1/2,abs}\) [๐Ÿ“–]
      • fasting: 15 min
      • fed: 43 min
    • \(C_{max}\)
    • F
      • 100% when dose of <20 mg
      • 54% when dose of 50 mg in patients with adrenal insufficiency [๐Ÿ“–]

Distribution

  • Parameters
    • \(V_{c}\)
      • 7 to 23.9 L iv
      • 28.4 L when dose of 50 mg in patients with adrenal insufficiency [๐Ÿ“–]
    • \(V_{c}/F\) or relative volume of distribution
      • 38.7-52.3 L patients with adrenal insufficiency
      • 17.5 ยฑ 10.5 L pediatric patients [๐Ÿ“–]
      • 27.1 ยฑ 8.4 L prepubertal
      • 49.5 ยฑ 12.2 L pubertal
      • 40.8 ยฑ 16.0 L prepubertal
    • \(V_{ss}\)
      • increasing with increasing doses [๐Ÿ“–]
      • 5 mg: 20.7 ยฑ 7.3 L
      • 40 mg: 37.5 ยฑ 5.8 L

Metabolism

  • [๐Ÿ“–]
    • 11ฮฒ-hydroxysteroid dehydrogenase
      • bidirectional
      • type 1 (11ฮฒ-HSD1) to cortisol liver and adipose
        • undetectable \(<3\) months
        • stabilized approx. at 12 months
      • type 2 (11-ฮฒHSD2) to cortisone in kidney
        • increased from 0-52 weeks,
    • 5ฮฑ-reductase(cortisol) and 5ฮฒ-reductase (cortisone)
      • unidirectional
        • low in newborns
        • highest activity >3 months
        • declined <52 weeks
        • similar 3.5-17.5 years
    • 3ฮฑ-hydroxysteroid
      • unidirectional
    • 6ฮฒ-hydroxylase (CYP3A4)
      • unidirectional
      • approx. 1%

Cortisol

Metabolic pathway of cortisol. Figures were adapted from PhD thesis of Johanna Melin. Created using diagrams.net

Elimination

  • At least 90% of cortisol and cortisone metabolites are normally excreted as sulfate or glucuronide conjugates. Conjugation of cortisol and cortisone can occur at the 21 position, and 3ฮฑ-reduced steroids can also be conjugated at the 3ฮฑ position
  • Parameters
    • \(CL\)
      • dose-dependent CL
      • lower in neonates (due to maturation of metabolic enzymes)
      • 12.5 to 20.2 L/h (iv 5-50 mg)
      • 12.5 L/h (iv 5 mg)
      • 17.6 L/h (iv 40 mg)
      • note: Saturation of CBG leads to \(CL_u\) increasing disproportionally with respect to \(CL_{tot}\).
      • CL (\(CL_u\)) remains constant, since it is independent of \(f_u\).
    • \(CL/F\)
      • 19.1 L/h (oral 10-20 mg: Fโ‰ˆ1)
      • 27.3 L/h (50 mg)
      • 12.4-25.6 L/h (patients with adrenal insufficiency)
      • note: highest value in pubertal patients
    • \(AUC\)
      • nonlinear processes (e.g. saturable plasma protein binding or saturable absorption)

Pharmacodynamics

  • Effect
    • endogenous cortisol synthesis
    • T cell dynamics [๐Ÿ“–]
  • correlation with 17-OHP concentration
    • 1 h post dose
    • delayed inhibitory effect with r=-0.302 [๐Ÿ“–]
  • no correlation between AUC for cortisol and 17-OHP [๐Ÿ“–]

Formulations and Administration

  • Lowest available dose for a oral tablet
    • 5 mg in USA
    • 10 mg in Europe or Canada

Infacort ยฎ

  • Diurnal Ltd
  • immediate-release hydrocortisone
  • Brand name: Alkindi (with four doses: 0.5 mg, 1 mg, 2 mg and 5 mg)
  • Approval for children with adrenal insufficiency from regulatory agencies [๐Ÿ“–]
    • EMA - 2018
    • FDA - 2020
  • oral (po)
  • hydrocortisone granules with taste masking
    • dry granules or mixed with a small amount of soft food
  • analysis in adults with a NCA by [๐Ÿ“–]
    • does not account for known nonlinearities of cortisol
  • good disease control with normal growth and no increased risk of adrenal crises [๐Ÿ“–]

Licensed Hydrocortisone tablet

  • Auden Mackenzie Ltd
  • oral (po)

Hydrocortisone Succinate

  • intravenous (iv) bolus
  • HC administration

Hydrocortisone cypionate suspension

  • Pharmacia & UpJohn
  • voluntarily recalled in July 2000 [๐Ÿ“–]
  • possible inaccuracies in preparations can lead to unanticipated adverse effects [๐Ÿ“–]