Efficacy and Hepatotoxicity During Rapid Titration of Ketoconazole and/or Metyrapone in Patients With Cushing Syndrome

Abstract

Context: Ketoconazole (KTZ) and metyrapone (MET) are used to normalize cortisol in Cushing syndrome (CS). Available recommendations can delay time to control.

Objective: This work aimed to identify predictors of treatment success and hepatotoxicity during rapid titration of KTZ and MET and to assess differences in blood pressure or potassium.

Methods: A retrospective evaluation was conducted at a tertiary referral center. Participants included 52 patients receiving treatment for adrenocorticotropin (ACTH)-dependent CS from 2004 to 2023. Interventions included KTZ or MET. The main outcome measures included the number of patients achieving target morning serum cortisol (AM F), defined as 12 mcg/dL or less (≤331 nmol/L), or increased liver function tests (LFTs) suggesting drug-induced liver injury (alanine/aspartate transaminase and alkaline phosphatase ≥3-fold upper limit of normal [≥3ULN], total bilirubin [Bili] ≥2ULN).

Results: KTZ achieved target AM F in 39% (95% CI 24%-56%) of patients, compared to 74% (95% CI 49%-90%) on MET. Lower baseline AM F predicted success only with MET. Among KTZ responders, maximal effect occurred by 2 days after a dose increase. LFTs worsened with KTZ and improved with MET. A similar proportion of patients had an LFT reach or exceed 3ULN with KTZ (22%; 95% CI 10%-39%) and MET (25%; 95% CI 4%-64%). Higher doses of KTZ, but not MET, predicted this. Bili reached or exceeded 2ULN in 3% (95% CI 0%-15%) of patients receiving KTZ and none receiving MET. Blood pressure and hypokalemia improved with KTZ but did not change with MET.

Conclusion: Hypercortisolism can likely be controlled faster with rapid titration of KTZ or MET. LFT abnormalities increased with KTZ but were common with MET treatment, likely reflecting underlying liver pathology in CS.

Keywords: Cushing; ectopic ACTH secretion; ketoconazole; metyrapone; treatment.

Figure 1.

Relative reduction of morning serum cortisol after initiation or dose increase of ketoconazole. Treatment response was defined as a 30% or greater reduction of baseline cortisol (dotted line) at any point after the dose increase. Numbers on the graph detail how many patients from each group had available data each day. Among 11 responders, 5 returned to more than 70% of baseline while receiving the same daily dose. Two of these exceeded their baseline after the final unchanged dose (168% and 117% of baseline), while the other 3 ended at 51%, 74%, and 78% of baseline.

Figure 2.

Suggested approach for initiation of ketoconazole or metyrapone in Cushing syndrome. Rapid dose titration based on morning serum cortisol is likely to shorten the time to control compared to the common clinical practice of dose adjustments 1 or more weeks apart based on UFC measurements. *Baseline UFC can be used to guide initial metyrapone dose as follows: UFC <6 × ULN − 500 mg daily; UFC 6-9 × ULN − 750 mg daily; UFC >9 × ULN − 1000 mg daily. Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CYP3A4, cytochrome P450 3A4; KTZ, ketoconazole; MET, metyrapone; UFC, 24-hour urine free cortisol; ULN, upper limit of normal.