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Table 3 Clinical pharmacokinetic profiles of medicines used for the treatment of hypercortisolism

From: Systemic therapy of Cushing’s syndrome

 

Aminoglutethimide

Cabergoline

Etomidate

Ketoconazole

Metyrapone

Trade name; sponsoring company

Orimeten; Novartis

Dostinex; Pfizer

Hypnomidate; Janssen-Cilag

Nizoral; Janssen-Cilag

Metopirone; HRA Pharma

European birth date

January 18, 1984

June 24, 2002

October 27, 1978

July 20, 1981

April 1, 1979

Cancer indication

Metastatic breast cancer

No

No

No

No

Cmax (μg/mL)

5.91

37 ± 8 pg/mL

N/A

3.5

3.72

tmax (h)

1.0 - 4.0

0.5 – 4.0

N/A

1.0 - 2.0

1.0

Bioavailability (oral, %)

92 – 98 systemic

N/A3[28]

N/A

N/A

N/A

Concomitant food intake effect on bioavailability

With food and water

No significant food effect

N/A

Maximal absorption with food

Recommended with milk or after a meal to minimize nausea and vomiting

Volume of distribution (L/kg) 70-kg subject assumed

N/A

N/A3[28]

4.5

N/A

N/A

Major metabolites

N-acetylaminoglutethimide (N-hydroxylaminoglutethimide **if enzyme induction occurs)

6-Allyl-8-β-carboxy-ergoline

N/A

Main metabolism is by oxidation and cleavage of the imidazole- and piperazine-ring systems by hepatic microsomal enzymes.

Metyrapol, an active alcohol metabolite, similar potency in inhibiting adrenal 11-β-hydroxylase

Plasma half-life (h)

12.5 ± 1.6

63 - 69

3 - 5

biphasic 2/8

20 - 26 minutes intravenous, ~2 h oral

Plasma protein binding (%)

21 – 25

41 - 424

76.5

99 (measured in vitro) mainly albumin

N/A

Empirical formula (g/mol)

C13H16N2O2 (232.3)

C26H37N5O2 (451.6)

C14H16N2O2 (244.3)

C26H28Cl2N4O4 (531.4)

C14H14N2O (226.3)

Mechanism of action

Inhibitor of cytochrome P450 (steroidogenesis and mineralocorticoidgenesis inhibitor)

Dopamine receptor agonist

Inhibits cortisol synthesis by inhibiting CYP11B1, and cytochrome P450scc [29]

Inhibitor of various subtypes of cytochrome P450 (steroidogenesis inhibitor);Inhibitor of side-chain cleavage complex, 17,20-lyase, 11-β-hydroxylase, 18- hydroxylase and 17-α-hydroxylase

Inhibits adreno-corticosteroid synthesis by blocking the 11-β-hydroxylase in the adrenal cortex

Clinical recommended dose

Adrenocortical-adenoma: 2 - 3 × 250 mg adrenocortical-carcinoma: 2 - 4 × 250 mg ectopic ACTH-syndrome: 4 - 7 × 250 mg

Initiation of therapy: 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice a week up to a dosage of 1 mg twice a week according to the patient’s serum prolactin level

Effective hypnotic dose: between 0.15 mg/kg and 0.30 mg/kg; doses of 0.04 – 0.05 mg/kg per h for hypercortisolemia patients [30]

1 × 200 mg q.d.

Daily dose: from 250 mg to 6 g; 6 four-hourly doses of 15 mg/kg, with a minimum dose of 250 mg5

Dosage form

Tablet

Tablet

Solution

Tablet

Capsule

Human AUC at the clinical dose

96.8 ng*h/mL

1295 ± 359.3 ng*h/mL [28]

N/A

N/A

N/A

 

Mifepristone

Mitotane

Pasireotide

Temozolomide

 

Trade name; sponsoring company

Corluxin; HRA Pharma

Lysodren; HRA Pharma

Signifor; Novartis

Temodal; Merck Sharp & Dohme

 

European birth date

August 25, 1999

April 28, 2004

April 24, 2012

January 26, 1999

 

Cancer indication

No

Adrenocortical carcinoma

No

Glioblastoma

 

Cmax (μg/mL)

1.98

13.06[31]

N/A

13.97[32]

 

tmax (h)

1.0 - 2.0

3.76[31]

0.25 - 0.5

0.5 – 1.5

 

Bioavailability (oral, %)

69 absolute by lower dose; higher dose 40

N/A

N/A

Essentially 1007[32]

 

Concomitant food intake effect on bioavailability

No significant food effect

With food and water

N/A

No information in SmPC

 

Volume of distribution (L/kg) 70-kg subject assumed

1.47 ± 0.25 [33]

N/A

Vz/F >100 Liter

0.397[32]

 

Major metabolites

RU 42633, RU 42698 and RU 42848

1,1-(o,p’-Dichlorodiphenyl-) ethanoic acid (o,p’-DDA)

N/A

5-Amino-imidazole-4-carboxamide (AIC) and Methyl-hydrazine

 

Plasma half-life (h)

90

18 - 159 days

~12

1.8

 

Plasma protein binding (%)

98

N/A

88

10 - 20

 

Empirical formula (formula weight g/mol)

C29H35NO2 (429.6)

C14H10Cl4 (320.0)

C59H67N9O9 (1046.2)

C6H6N6O2 (194.2)

 

Mechanism of action

Competitive progesterone receptor antagonist

Precise mechanism of action is not known, but an adrenal inhibition is suspected

Binding to four of five somatostatin receptors; (SSTR-1,-2,-3,-5) [34]

After poisoning of TMZ to active metabolite MTIC, alkylation of Guanine-residues at N-7

 

Clinical recommended dose

600 mg

Patients are titrated to reach 14 - 20 mg/L plasma concentration starting with 2 - 3 g daily

0.6 mg b.i.d. (0.3 or 0.9 mgdose adaption)8

Initially 200 mg/m2 daily (pretreated patients: 150 mg/m2 daily)

 

Dosage form

Tablet

Tablet

Subcutaneous injection

Capsule

 

Human AUC at the clinical dose

0.67 ± 0.21 μmol/l*h/mg9[35]

N/A

54.1 ± 7.0 ng*h/mL10[36]

33.2 μg*h/mL12[32]

 
  1. Abbreviations: AUC, area under the curve; b.i.d., twice daily; Cmax, maximal plasma concentration; q.d., every day; tmax, time after administration when Cmax is reached; 1500 mg; 2750 mg administration; 3n = 12, dose = 0.5 mg; 4in-vitro study with concentrations of 0.1 - 10 ng/ml; 5pediatric population; 6measured in dogs, 50 mg/kg, tablets in food; 7200 mg/m2; 8also available as long-acting release formulation in the strengths 20, 40, 60 mg; 9AUC0-inf; 10AUC0–24 h: 600 μg q.d. (n = 11); 1130 mg single dose in 24 healthy volunteers; 12AUC0–24 h; source of information: SmPCs of the corresponding medicines unless otherwise indicated (if not licensed for treatment of CS, then in other indication; i.e. Ketoconazole, Etomidate, and Temozolomide). If not marketed any more (Aminoglutethimide) the last approved SmPC was used.