Pharmaceutical Sciences 藥物科學Ketoconazole 用於治療庫欣氏症候群 員生醫院藥劑課藥師江姿宜 童玟津 摘要 (Cushing's syndrome, CS) ketoconazole mifepristone (Korlym) pasireotide (Signifor) Cushing's syndrome hypercortisolism medical therapy ketoconazole 壹 前言 (hypercortisolism) CS (ACTH) CS CS (Cushing's disease) (ectopic) ACTH CS 1 貳 主要適應症 ACTH 2 參 藥品種類 38 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.3 Sep. 30 2014
Ketoconazole enzyme inhibitors) aminoglutethimide ketoconazole metyrapone trilostane fluconazole etomidate ketoconazole aminoglutethimide (sidechain cleavage) 11 -hydroxylase 18-hydroxylase trilostane fluconazole 1,2 etomidate ketoconazole metyrapone 2 FDA (off-label use) metyrapone (hypothalamic-pituitary ACTH) 3 二 抑制腎上腺劑 (adrenolytic agents) Mitotane FDA (adrenal cortical carcinoma) 3 ACTH 2,4 三 神經調節藥 (neuromodulatory drugs) bromocriptine cyproheptadine valproate pasireotide cabergoline 藥物科腎上腺酶抑制劑 (adrenal (somatostatin analogue) 學一 pasireotide (dopamine agonist) cabergoline 1,2 pasireotide (Signifor) 2012 12 FDA 3 四 糖皮質激素受體拮抗劑 (glucocorticoid-receptor antagonists) Mifepristone (RU-486) (antiprogestational) 2 mifepristone (Korlym) 2012 2 FDA 3 肆 各藥品之作用機轉與不良反應一 Ketoconazole Ketoconazole (cortisol) CYP11A1 side-chain cleavage CYP11B1 11-deoxycortisol cortisol 2,5 C17-20 desmolase (androstenedione) (testosterone) 200 400 mg corticotroph adenylate cyclase ACTH 2,5 ketoconazole estradiol testosterone 藥學雜誌 120 39 303 Sep. 30 2014
藥Pharmaceutical Sciences 物科學2,5 Ketoconazole C 2,3,5 Ketoconazole 2013 7 FDA (box warning) 2,3,5 二 Metyrapone Metyrapone CYP11B1 (11-beta-hydroxylase) ACTH (compensatory) (androgen) 2,5 Metyrapone 2,5 Metyrapone CYP11B2 ( ) (aldosterone) 11-deoxycorticosterone (mineralocorticoid) 2,5 三 Etomidate Etomidate imidazole CYP11B1 CYP11A1 ACTH () 2,5 2,5 四 Mitotane Mitotane (adrenolytic activity) CYP11B1 (CYP11A1) mitotane acyl chloride 2,5 Mitotane cortisol 17-hydroxycorticosteroids (17-OHCS) 50% 80% cortisol 6-beta-hydroxycortisol 17-OHCS 24 mitotane 2 mitotane 2 mitotane (glucocorticoids) dexamethasone fludrocortisone prednisolone (adrenal insufficiency) mitotane (zona glomerulosa) mitotane (stress-related adrenal crisis) 2,5 (cortisol-binding globulin CBG) hormone-binding globulin 40 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.3 Sep. 30 2014
Ketoconazole 藥物科學2 CBG (sex hormonebinding globulin SHBG) (thyroid hormone-binding globulin TBG) 2 mitotane 2 3 g 5 mitotane 2 五 Cabergoline Cabergoline dopaminergic ergoline corticotroph tumors D2 ACTH 6,7 6,7 六 Pasireotide Pasireotide 5 (somatostatin receptor subtype 5) ACTH (corticotrophin) corticotropes 2,3 3 (incretin) (glucagonlike peptide-1 [GLP-1] glucose-dependent insulinotropic polypeptide [GIP]) 2 藥學雜誌 120 41 七 Mifepristone Mifepristone (GR-II) Mifepristone GR-II GR-I (mineralocorticoid MR) 3 24 (openlabel) 46 mifepristone 300 1200 mg/ 87% 8 3,8 伍 臨床應用與建議 (block and replace) (normalization) 2 ketoconazole 200 mg () 400 mg () ketoconazole PPI (proton pump inhibitor) H2 303 Sep. 30 2014
藥Pharmaceutical Sciences 物科學2,5 50% ketoconazole ALT ketoconazole ketoconazole CYP3A4 CYP3A4 2,5 ( ) 2,3,6,8,9 11 mitotane metyrapone ketoconazole 10 17 Cushing's disease (29% pasireotide) (53% pasireotide cabergoline) (88% pasireotide cabergoline ketoconazole) 11 cabergoline ketoconazole 7 陸 結語 ketoconazole 2,3,6,8,9 表一庫欣氏症候群輔助治療用藥 Ketoconazole 200 mg BID TID400 mg TID Metyrapone 250 mg BID TID 4.5 g/ ( 2 g/ ) Etomidate 0.3 mg/kg/hr 10 Mitotane 0.5 g 0.5 g 2 3 g/ (Mitotane 6 9 mititane Cabergoline 0.5 1 mg 6 mg Pasireotide 0.6 0.9 mg0.3 0.9 mg Child Pugh B 0.3 mg 0.6 mg Child Pugh C FDA 42 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.3 Sep. 30 2014
Ketoconazole Mifepristone 300 mg 1200 mg/ 20 mg/kg/ 600 mg/600 mg/ Ketoconazole for the Treatment of Cushing's Syndrome Zi-Yi Jiang, Wen-Jin Tung Department of Pharmacy, Yuan Sheng Hospital FDA pasireotide (Signifor) (Cushing's disease) 0.3 mg/ml 0.6 mg/ml 0.9 mg/ml Abstract The medical therapy of Cushing's syndrome includes four major categories: adrenal enzyme inhibitors, adrenolytic agents, neuromodulatory drugs, glucocorticoid-receptor antagonists. The adrenal enzyme inhibitors-ketoconazole is recommended as the first drug used. Mifepristone (Korlym) and pasireotide (Signifor) have been approved in the United States by the Food and Drug Administration for this indication. Since limited monotherapy effect of hypercortisolism, the combinations of these drugs often have additive or synergistic therapeutic effects at lower individual doses, thereby minimizing side effects. 藥學雜誌 120 43 藥物科學參考資料 : 1. Feelders RA, Hofland LJ, de Herder WW Medical treatment of Cushing's syndrome: adrenal-blocking drugs and ketaconazole. Neuroendocrinology 2010; 92 Suppl 1:111. 2. Lynnette K Nieman Medical therapy of hypercortisolism (Cushing's syndrome). UpToDate 2014. 3. Drugs @FDA FDA Approved Drug Products and drug package insert. 4. Baudry C, Coste J, Bou Khalil R, et al: Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol 2012; 167:473. 5. Andre Lacroix Pharmacology and toxicity of adrenal enzyme inhibitors and adrenolytic agents. UpToDate 2014. 6. Godbout A, Manavela M, Danilowicz K, et al: Cabergoline monotherapy in the long-term treatment of Cushing's disease. Eur J Endocrinol 2010; 163:709. 7. Barbot M, Albiger N, Ceccato F, et al: Combination therapy for Cushing's disease: effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole? Pituitary 2013. 8. Fleseriu M, Biller BM, Findling JW, et al: Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab 2012; 97:2039. 9. Preda VA, Sen J, Karavitaki N, et al: Etomidate in the management of hypercortisolaemia in Cushing's syndrome: a review. Eur J Endocrinol 2012; 167:137. 10. Kamenický P, Droumaguet C, Salenave S, et al: Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTHdependent Cushing's syndrome. J Clin Endocrinol Metab 2011; 96:2796. 11. Feelders RA, de Bruin C, Pereira AM, et al: Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N Engl J Med 2010; 362:1846. 303 Sep. 30 2014