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General Description:

Levoketoconazole, identified by CAS number 142128-57-2, is a notable compound with significant therapeutic applications. Cushing's syndrome (CS) is underpinned by chronic hypercortisolism leading to multisystem morbidity, including effects on the cardiovascular and endocrine systems, metabolic syndrome with accompanying changes in body composition, neuropsychiatric effects, changes in blood pressure and chemistry, and opportunistic infections. has been used both on- and off-label to treat CS due to its ability to inhibit cortisol production. Still, toxicity has limited its use, notably hepatic toxicity and a tendency to prolong the QT interval. Levoketoconazole is one of two enantiomers present in racemic . It possesses most of the inhibitory effect towards steroidogenic enzymes, making it an attractive candidate for CS treatment with a potentially lower toxicity profile than its racemate. Levoketoconazole was approved by the FDA on December 30, 2021, and is currently marketed under the registered trademark RECORLEV by Xeris Pharmaceuticals, Inc.

Indications:

This drug is primarily indicated for: Levoketoconazole is indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative. Levoketoconazole is not indicated for the treatment of fungal infections. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Levoketoconazole undergoes metabolic processing primarily in: No _in vitro_ or _in vivo_ studies of levoketoconazole metabolism have been performed. is known to be hepatically metabolized to several inactive metabolites, mainly through oxidation of the imidazole and piperazine rings, together with oxidative O-dealkylation and aromatic hydroxylation. Levoketoconazole is known to both induce and strongly inhibit CYP3A4. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Levoketoconazole are crucial for its therapeutic efficacy: Levoketoconazole has a T_max of ~1.5-2 hours regardless of dose, while the C_max increases proportionally with the dose. The AUC increases greater than dose proportionally over the recommended range of 150-600 mg. Co-administration of a single 600 mg oral dose with a high-fat meal increased the AUC by 30% with no change in C_max and a delay in the median T_max from two to four hours. The pharmacokinetics of racemic are not significantly different in patients with renal impairment; given the extensive hepatic metabolism of , it is expected that hepatic impairment will affect the pharmacokinetics of levoketoconazole. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Levoketoconazole is an important consideration for its dosing schedule: Levoketoconazole has a plasma elimination half-life of 3-4.5 hours following a single dose and 4-6 hours following multiple doses. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Levoketoconazole exhibits a strong affinity for binding with plasma proteins: Levoketoconazole is 99.3% bound to human plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Levoketoconazole from the body primarily occurs through: Approximately 13% of racemic is excreted in the urine, 2-4% as unchanged drug, while the major excretion route is in the feces, accounting for ~57%. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Levoketoconazole is distributed throughout the body with a volume of distribution of: Levoketoconazole has an apparent volume of distribution of 31-41 L, approximating total body water. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Levoketoconazole exerts its therapeutic effects through: Levoketoconazole is a steroidogenic inhibitor that reduces morbidity and mortality due to hypercortisolism associated with Cushing's syndrome. Due to its mechanism of action, levoketoconazole may cause hypocortisolism and decreased serum testosterone levels in both sexes. Levoketoconazole is known to cause dose-dependent increases in the QTc interval; at dose levels between 150 and 600 mg twice daily, the largest mean increase in the QTc was 24 msec. Hypersensitivity to levoketoconazole has been observed, and anaphylaxis has been reported with the racemic . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Levoketoconazole functions by: Cushing's syndrome (CS) is underpinned by chronic hypercortisolism leading to multisystem morbidity, including effects on the cardiovascular and endocrine systems, metabolic syndrome with accompanying changes in body composition, neuropsychiatric effects, changes in blood pressure and chemistry, and opportunistic infections. CS is most commonly caused by an ACTH-producing pituitary adenoma (ACTH-dependent CS) but may also be caused by an adrenal adenoma, adrenal carcinoma, or adrenal hyperplasia (ACTH-independent CS). As hypercortisolism is associated with significant morbidity and increased mortality, the primary goal of therapy is to normalize cortisol levels, either through surgical resection of the associated tumour or, when surgery is unsuccessful or inappropriate, radiological or chemotherapeutic treatment. Different medications target different axes of the underlying etiology of CS; steroidogenic enzyme inhibitors are effective against all forms of CS. , which is indicated for endogenous CS by the EMA and used for the same indication off-label in the US, is a racemate of 2S,4R (levoketoconazole) and 2R,4S (dextroketoconazole) _cis_-enantiomers known to inhibit multiple CYP450 enzymes. Studies using enantiomerically pure versions deduced that levoketoconazole is between 1.2-2.7 times more potent at inhibiting the key steroidogenic enzymes CYP11A1, CYP11B1, CYP11B2, and CYP17A1 than racemic , and ~15-25 times more potent than dextroketoconazole, suggesting that the majority of the therapeutic efficacy of in CS is due to levoketoconazole. Hence, levoketoconazole directly inhibits key enzymes in cortisol and testosterone synthesis. As levoketoconazole is a more potent steroidogenic inhibitor than , lower concentrations should achieve the same therapeutic effect and may also decrease the risk of hepatic toxicity. In addition to the dose consideration, levoketoconazole is 12 times less potent than dextroketoconazole at inhibiting CYP7A1, a rate-limiting enzyme for bile acid synthesis. However, levoketoconazole is roughly two times more potent at inhibiting CYP3A4 than dextroketoconazole. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Levoketoconazole belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group, classified under the direct parent group Phenylpiperazines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Diazinanes class, specifically within the Piperazines subclass.

Categories:

Levoketoconazole is categorized under the following therapeutic classes: Antifungal Agents, Azole Antifungals, Cortisol Synthesis Inhibitors, Cytochrome P-450 CYP1A2 Inducers, Cytochrome P-450 CYP1A2 Inducers (strength unknown), Cytochrome P-450 CYP2B6 Inhibitors, Cytochrome P-450 CYP2B6 Inhibitors (strength unknown), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 CYP3A4 Inhibitors (strong), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inducers, Cytochrome P-450 CYP3A5 Inducers (strength unknown), Cytochrome P-450 CYP3A5 Inhibitors, Cytochrome P-450 CYP3A5 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, MATE 1 Inhibitors, MATE inhibitors, OCT2 Inhibitors, P-glycoprotein inhibitors, QTc Prolonging Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.