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

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.