Reversible Adrenal Insufficiency
`Induced by Ketoconazole
`
`W. Stuart Tucker, Jr, MD; Barbara B. Snell, MD; Donald P. Island; Clark R. Gregg, MD
`
`KETOCONAZOLE, an imidazole anti-
`fungal drug, blocks testicular and
`adrenal steroid synthesis in a dose-
`dependent and time-dependent man-
`ner, presumably correlating with
`serum levels of ketoconazole.1-5 Al-
`though hypogonadism and gyneco-
`mastia caused by ketoconazole have
`been reported, symptomatic hypo-
`adrenalism has not yet been de-
`scribed,1,4,6 to
`the
`best
`of
`our
`knowledge. We report a patient who
`developed symptoms and signs of
`hypoadrenalism while receiving an
`experimentally high daily dose of
`ketoconazole. The results of serum
`and urinary steroid measurements
`impression.
`confirmed this clinical
`All symptoms and signs of adrenal
`insufficiency resolved promptly fol-
`lowing discontinuation of ketocona-
`zole therapy.
`
`Methods
`A one-hour intravenous adrenocortico-
`tropic hormone (ACTH) (cosyntropin [Cor-
`trosyn])
`test,7
`a 48-hour
`intravenous
`ACTH (Cortrosyn) test,8 and a metyrapone
`(Metopirone) test' were performed during
`ketoconazole therapy and were repeated
`after its discontinuation.
`
`From the Divisions of Endocrinology (Dr Tucker
`and Mr Island) and Infectious Diseases (Dr Gregg),
`of Medicine, Vanderbilt University
`Department
`School of Medicine, Nashville, Tenn. Dr Snell
`is in
`private practice in Nashville, Tenn. Dr Tucker is now
`with The Nalle Clinic, Charlotte, NC.
`Read in part before the 83rd annual meeting of
`for Microbiology, New
`the American Society
`Orleans, March 9, 1983.
`Infectious Dis-
`requests to Division of
`Reprint
`eases, Department of Medicine, St Thomas Hospital,
`PO Box 380, Nashville, TN 37202 (Dr Gregg).
`
`Report of a Case
`A hypertensive 48-year-old black man
`had an average blood pressure of 140/90
`mm Hg with methyldopa (Aldomet), 500
`mg/day, and a combination of triamter-
`ene, 50 mg, and hydrochlorothiazide, 25
`mg (Dyazide), 2 capsules per day, and
`sodium restriction. He acquired pulmo¬
`nary blastomycosis and was treated with
`ketoconazole (Nizoral), 800 mg orally at 6
`am daily on an experimental protocol. In
`the third week of this therapy, he devel¬
`oped emotional lability, depression, gener¬
`alized weakness, malaise, anorexia, and
`orthostatic dizziness. He also noted that
`time in his life he had a
`for the first
`suntan. He denied abdominal pain or other
`gastrointestinal complaints.
`Physical examination revealed relative
`hypotension with blood pressures mea¬
`sured as low as 100/60 mm Hg. There was
`hyperpigmentation of the anterior thighs,
`with a "suntan line" where the edge of his
`shorts had been. There was no other
`hyperpigmentation. His weight was con¬
`stant. Although he had mild hyponatremia
`(serum sodium level, 132 to 136 mEq/L)
`throughout therapy, this was not different
`from his serum sodium concentrations
`before or after the period of ketoconazole
`therapy. Neither gynecomastia, hyper-
`kalemia, hypoglycemia, nor eosinophilia
`developed.
`After discontinuation of both methyldo¬
`pa and sodium restriction and after reduc¬
`tion of the triamterene/hydrochlorothia-
`zide dose to 1 capsule per day, his blood
`pressure averaged 125/70 mm Hg for the
`the course of ketoconazole.
`duration of
`Coincident with peak serum ketoconazole
`levels on day 32, a morning plasma cortisol
`level was low and a one-hour ACTH test
`result was abnormal, supporting a diagno¬
`insufficiency (Table).
`sis of adrenal
`During a 48-hour ACTH test on days 41
`
`through 43 and during a metyrapone test
`on days 173 through 175, 17-hydroxyste-
`roid excretion was low, but measurements
`of urinary free cortisol and tetrahydro-
`levels, respectively, demon¬
`deoxycortisol
`strated adrenal reserve (Table). Because
`his symptoms improved during continued
`ketoconazole therapy and because he had
`levels of 11 and 14
`early morning cortisol
`Mg/dL coincident with trough ketoconazole
`concentrations (Table), he did not receive
`glucocorticoid therapy. The mean of 12
`peak ketoconazole serum levels deter¬
`mined two hours after daily oral doses was
`11.3 pg/mL. His pulmonary infiltrates
`cleared completely, and ketoconazole ther¬
`apy was discontinued after 187 days of
`treatment. Within days, his symptoms
`completely resolved, and his blood pres¬
`sure rose to 160/100 mm Hg. The same
`antihypertensive regimen that he had fol¬
`lowed prior to ketoconazole therapy stabi¬
`lized his blood pressure at 140/95 mm Hg.
`On days 38, 46 through 48, and 54 through
`56 after ketoconazole therapy was stopped,
`one-hour ACTH, 48-hour ACTH, and
`metyrapone tests were normal, respective¬
`ly (Table).
`
`Comment
`Since discontinuation of ketocona¬
`zole therapy led to prompt resolution
`of symptoms and signs of hypoadren-
`alism, and since pituitary-adrenal
`function was then proven to be nor¬
`mal, ketoconazole and not blastomy-
`cotic adrenalitis was the likely cause
`insufficiency demon¬
`of
`the adrenal
`strated in our patient. Lack of inter-
`illness,
`treatment with a
`current
`potassium-sparing diuretic, or un¬
`known effects of ketoconazole on
`aldosterone synthesis may account
`for the absence of hyponatremia and
`
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`
`
`JANSSEN EXHIBIT 2090
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`Tests ot Pituitary-Adrenal Function
`
`With Ketoconazole Without Ketoconazole
`Therapy
`Therapy
`Normal
`Values Day O Day 1 Day 2 Day O Day 1
`
`Day 2
`
`-hr Adrenocorticotropic hormone
`test
`Plasma cortisol
`(morning), MQ/rJL
`Time 0
`At
`1 hr
`48-hr Adrenocorticotropic hormone
`infusion lest
`Plasma cortisol
`(morning), ng/dL
`Urinary steroids (24 hr)
`17-Hydroxysteroids, mg/g of
`creatinine
`Free cortisol, M9
`Tetrahydrodeoxycortisol, mg
`Metyrapone test
`Plasma cortisol
`(morning), ^g/dL
`Plasma adrenocorticotropic hor¬
`mone (morning). pg/mL
`Urinary steroids (24 hr)
`17-Hydroxysteroids, mg/g of
`creatinine
`Free cortisol, M9
`Tetrahydrodeoxycortisol, mg
`
`6-20
`
`111
`
`38
`
`24
`
`67
`
`3-7
`20-90
`<1
`
`6-20
`
`0-120
`
`3-7
`20-90
`<1
`
`1.6
`19
`0.9
`
`14t
`
`70t
`
`2.9
`25
`1.2
`
`13
`567
`6.5
`
`18.2
`801
`12
`
`3.7
`45
`1
`
`21.8
`2,250
`9
`
`34.9
`2,600
`13
`
`19
`
`550
`
`15
`
`15
`
`45
`
`390
`
`3.3
`11
`3.7
`
`6.7
`11
`10.6
`
`4.1
`66
`1
`
`5.8
`28
`7.4
`
`11.7
`20
`22
`
`•Coincident with peak serum ketoconazole concentration.
`tCoincident with trough serum ketoconazole concentration.
`
`hyperkalemia typical of adrenocorti-
`cal failure.
`The experimentally high dose of
`ketoconazole used in our patient may
`explain the lack of more widely recog¬
`nized hypoadrenalism from ketocona¬
`zole in usual practice, where doses
`and serum levels are lower. Also,
`because the usual morning dosing of
`ketoconazole results in peak serum
`levels after maximal diurnal cortisol
`production has occurred during the
`early morning hours, more profound
`hypoadrenalism with addisonian cri¬
`sis is perhaps avoided. Symptoms of
`hypoadrenalism have not been de¬
`tected in prospective studies of pa¬
`tients treated with similarly high
`ketoconazole.' However,
`doses
`of
`there may be variation among indi¬
`viduals in their susceptibility to these
`effects, and Pont et al' suggest that
`patients taking high doses of keto¬
`conazole be considered at
`risk for
`insufficiency.
`symptomatic adrenal
`there may have been
`Interestingly,
`physiologic compensation for the hy¬
`poadrenalism in our patient as indi¬
`cated by the spontaneous clinical
`
`improvement and by the trend toward
`higher values of serum cortisol and
`urinary steroid excretion with contin¬
`ued ketoconazole therapy (Table). Al¬
`though Pont et alJ noted a possible
`partial reversal of suppression of tes¬
`tosterone secretion with more pro¬
`longed ketoconazole therapy, they did
`not find a correlation of duration of
`ketoconazole and its degree of sup¬
`pression of adrenal steroidogenesis.
`In vitro, ketoconazole inhibits adre¬
`nal P450-dependent mitochondrial
`enzymes performing cholesterol side-
`chain cleavage and ll-ß-hydroxyla-
`tion."'" Comparison of the 17-hydrox-
`ysteroid and tetrahydrodeoxycortisol
`excretion while the patient was
`receiving ketoconazole and later while
`not taking ketoconazole during mety¬
`rapone testing (Table) suggests that
`metyraponelike inhibition of 11-0-
`hydroxylase is not the primary site of
`ketoconazole's interference in cortisol
`synthesis. Rather, ketoconazole seems
`to exert its principal inhibitory effect
`at an earlier step in the biosynthetic
`pathway. That the ability of ketocon¬
`azole to inhibit adrenal steroid syn-
`
`thesis is additive with the effect of
`metyrapone is supported by our find¬
`ing that the ACTH levels were much
`higher before and after metyrapone
`testing while the patient was taking
`ketoconazole than when he was not
`taking ketoconazole.
`In summary, ketoconazole adminis¬
`tered in experimentally high doses
`resulting in high serum levels can
`inhibit adrenal steroidogenesis, which
`rarely may cause clinically apparent
`hypoadrenalism. This inhibitory ef¬
`fect may be partially overcome by
`compensatory mecha¬
`endogenous
`nisms and is totally reversible with
`discontinuation of ketoconazole ther¬
`apy.
`
`Ketoconazole was supplied free of charge by
`Janssen Pharmaceutics Inc, Piscataway, NJ.
`The authors acknowledge Barbara G. McCord,
`who prepared the manuscript, and David N.
`Orth, MD, who provided valuable advice on the
`laboratory evaluation of pituitary-adrenal func¬
`tion. We extend special
`thanks to Lawrence K.
`Wolfe, MD, for his critique of the manuscript.
`This patient was treated under the National
`Institutes of Health-National Institute of Aller¬
`gy and Infectious Diseases Mycoses Study Group
`Phase III Study on ketoconazole in the therapy
`of histoplasmosis and blastomycosis.
`
`References
`1. Pont A, Williams PL, Loose DS, et al:
`Ketoconazole blocks adrenal steroid synthesis.
`Ann Intern Med 1982;97:370-372.
`2. Pont A, Williams PL, Azhar S, et al:
`Ketoconazole blocks testosterone synthesis. Arch
`Intern Med 1982;142:2137-2140.
`3. Pont A, Graybill JR, Craven PC, et al:
`High-dose ketoconazole therapy and adrenal and
`testicular function in humans. Arch Intern Med
`1984;144:2150-2153.
`4. Schurmeyer T, Nieschlag E: Ketoconazole-
`induced drop in serum and saliva testosterone.
`Lancet 1982;2:1098.
`5. Santen RJ, Brugmans J, Symoens J, et al:
`Ketoconazole inhibits androgen production by
`blocking the 17-hydroxyprogesterone aldolase
`(C17-20 lyase) enzyme, abstracted. Clin Res
`1983;31:473A.
`6. Graybill JR: Summary: Potential and prob-
`lems with ketoconazole. Am J Med 1983;74:86\x=req-\
`90.
`7. Baxter JD, Tyrrell JB: The adrenal cortex,
`in Felig P, Baxter JD, Broadus AE, et al (eds):
`Endocrinology
`and Metabolism. New York,
`McGraw-Hill Book Co, 1981, p 443.
`8. Rose LI, Williams GH, Jagger PI, et al: The
`48-hour adrenocorticotrophin infusion test
`for
`insufficiency. Ann Intern Med
`adrenocortical
`1970;73:49-54.
`9. Liddle GW: The adrenals, in Williams RH
`(ed): Textbook of Endocrinology, ed 6. Philadel-
`phia, WB Saunders Co, 1981, pp 264-265.
`10. Kowal J: The effects of ketoconazole on
`steroidogenesis in cultured mouse adrenal cortex
`tumor cells. Endocrinology 1983;112:1541-1543.
`11. Loose DS, Kan PB, Hirst MA, et al:
`Ketoconazole blocks adrenal steroidogenesis by
`inhibiting cytochrome P450-dependent enzymes.
`J Clin Invest 1983;71:1495-1499.
`
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