7302 Efficacy And Hepatotoxicity Of Ketoconazole In Cushing’s Syndrome
Authors: Elenius Henrik , McGlotten Raven , Tewari Sharma Susmeeta , Nieman Lynnette K 
Published: October 2024

Disclosure: H. Elenius: None. R. McGlotten: None. S.T. Sharma: None. L.K. Nieman: None.

Medical therapy (Rx) of Cushing’s Syndrome (CS) is complicated by variable efficacy, delays to treatment goal and adverse reactions. Ketoconazole (KTZ) use is limited by hepatotoxicity. We retrospectively reviewed records of 65 inpatients receiving KTZ for CS between 2004-2023 to assess efficacy and hepatotoxicity. 24-hour urinary free cortisol (UFC), AM serum cortisol (F), liver function tests (LFTs: alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP)) and daily doses of KTZ were noted. Patients were excluded if they received other medical Rx for CS or strong CYP3A4 inducers/inhibitors; baseline (base) or endpoint F/LFTs were unavailable; or if they received KTZ within 4 days prior to base labs. 35 patients (pts) were evaluated for efficacy. Treatment success was defined as F ≤12 mcg/dL. 17 pts (49%) achieved goal F at a median of 3 days (1-11, IQR 2.5-5.5). Compared to uncontrolled pts, there was no difference in Rx duration, base UFC or F, or initial or final KTZ doses, including when adjusted for base UFC, F, weight or body surface area. The absolute and percent dose increases and the F level prompting an increase did not differ between groups. Pts who reached goal had fewer days (d) between dose increases than uncontrolled pts (median 2 vs 4 d, p=0.025). Of 19 pts on a stable KTZ dose for ≥3 d after an increase, mean F decreased from d 0 to d +1 (-19%, p=0.01), +3 (-38%, p=0.0001) and +4 (-25%, p=0.04). D +3 F decreased from d +1 (-14%, p=0.03) and +2 (-13%, p=0.03). After d+3 no further reduction was seen (but likely biased by subsequent dose changes or discharge after d +3). 37 pts were evaluated for toxicity during KTZ Rx. Of 3 pts with a base LFT ≥3 times upper limit of normal (3ULN), LFTs rose ≥30% in 1, improved to &lt;3ULN in 1 and did not change in the last pt. Of 34 pts with base LFTs &lt;3ULN, a ≥30% rise of ≥1 LFT was seen in 27. Of these, 10/27 had ≥1 LFT rise to ≥3ULN after a minimum cumulative dose of 3400 mg and at least 4 days of Rx. Compared to the other 24, these 10 pts had higher means of base AST (75 vs 54% of ULN, p=0.046), cumulative KTZ doses (10080 vs 4071 mg, p=0.0015), and daily KTZ doses (927 vs 650 mg, p=0.004). AST and ALT increased by ≥30% before ALP (AST vs ALP: 4 vs 6 d, p=0.08). After KTZ was stopped or reduced, LFTs reached &lt;3ULN at a median of 3 days (1-10, IQR 1.5-8.5) in 9 pts; pt 10 improved by discharge. 15/27 with an LFT rise ≥30% continued the same KTZ dose; LFTs stayed ≤ULN in 8, rose to &gt;ULN in 5 and improved from base &gt;ULN to ≤ULN in 2. By the end of inpt KTZ Rx (median 6 d, range 1-27, IQR 4-9), 13 pts (35%) had ≥1 LFT rise from ≤ULN to &gt;ULN, 4 (11%) had ≥1 LFT improve from &gt;ULN to ≤ULN. 12 stayed &gt;ULN (32%); 8 (22%) stayed ≤ULN. Our data supports raising KTZ doses every 72 hours for rapid control. Base AST correlates with liver toxicity risk and tends to rise before ALP. An LFT rise ≥30% is seen in most pts and should not prompt Rx cessation if &lt;3ULN. KTZ improves LFTs in a minority of pts, likely from cortisol reduction.

Presentation: 6/3/2024