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Endocrine Abstracts (2016) 41 GP158 | DOI: 10.1530/endoabs.41.GP158

Pituitary - Clinical

Differentiated pharmacokinetics of levoketoconazole (COR-003), the single 2S,4R-enantiomer of ketoconazole, a new investigational drug for the treatment of Cushing’s syndrome

Ruth Thieroff-Ekerdt1 & Diane Mould2

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1Strongbridge Biopharma, Trevose, Pennsylvania, USA; 2President Projections Research, Inc., Phoenixville, Pennsylvania, USA.


Ketoconazole is a 50/50 racemic mixture of two enantiomers (2S,4R and 2R,4S) used off label in the US for the treatment of endogenous Cushing’s syndrome by virtue of adrenal cortisol synthesis inhibition.

COR-003 (levoketoconazole) is the more potent single (2S,4R) enantiomer of ketoconazole (KTZ) to inhibit adrenal cortisol synthesis and is currently being investigated in a multinational Phase 3 study for the treatment of endogenous Cushing’s syndrome.

In a three period cross-over study in 24 healthy subjects dosed with ketoconazole at an oral dose of 400 mg QD, plasma concentrations of the two enantiomers were measured on Day 5 after 4 day QD oral dosing with 400mg ketoconazole and a single 80-mg dose of atorvastatin on Day 5. Maximal plasma concentrations of the 2S, 4R enantiomer were about three-fold higher (6.1 μg/ml, coefficient of variation 40.7%) than those of the 2R, 4S enantiomer. This pattern was also observed in a Phase 2a study in 37 patients with type 2 diabetes mellitus dosed for 14 days with 400 mg QD oral ketoconazole. PK data of KTZ, COR-003 and 2R, 4S were modeled using a population approach with the software package NONMEM version 7.2. PK modeling of KTZ, COR-003 and 2R, 4S suggested dose-proportional exposure for all analytes and linear PK, and revealed a greater clearance of 2R, 4S and a monophasic plasma-time curve of COR-003 in contrast to KTZ with two peaks.

Study treatments were safe and well tolerated. Headache, nausea, diarrhea, and back pain were the most frequently reported AEs.

Taken together, PK data show that COR-003 reaches higher plasma concentrations with reduced clearance compared to 2R,4S, potentially indicating reduced hepatic metabolism. Mechanistic nonclinical studies are being conducted to further investigate the differentiated PK profile of COR-003 and implications for hepatotoxicity and efficacy.

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