Levoketoconazole

Abstract

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Generic Name: LEVOKETOCONAZOLE

Proprietary Name: Recorlev (Xeris Pharmaceuticals)

Approval Rating: 2S (Orphan)

Therapeutic Class: Cortisol Synthesis Inhibitor

Similar Drugs: Ketoconazole, Osilodrostat

Sound-/Look-Alike Names: Ketoconazole, Levofloxacin, Levobunolol, Levocetirizine, Recort

Indications

Levoketoconazole is Food and Drug Administration (FDA) approved for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative. Levoketoconazole is not approved for the treatment of fungal infections. ¹

Cushing syndrome is a rare endocrine disease characterized by chronic overproduction of cortisol and associated with significant comorbidities and increased mortality, mainly due to cardiovascular disease. First-line therapy is usually surgery; however, medical therapy is often needed when surgery is delayed, contraindicated, or unsuccessful. Pharmacotherapy options vary regarding site of action and include pituitary-targeted agents, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists. Steroidogenesis inhibitors such as ketoconazole act by inhibiting 1 or more enzymes required for cortisol synthesis.^2,3 Ketoconazole has been used off label in the United States for the treatment of Cushing syndrome; however, use is associated with hepatotoxicity, QT prolongation, and hypogonadism in males.^3-8

Table 1 compares select agents used to treat Cushing syndrome.^1,9,10

Table 1.

Comparison of Select Agents Used to Treat Cushing Syndrome.^1,9,10

	Levoketoconazole	Ketoconazole	Osilodrostat
Brand name (manufacturer)	Recorlev (Xeris Pharmaceuticals)	(Various)	Isturisa (Recordati Rare Diseases)
Drug class	Cortisol synthesis inhibitor	Antifungal	Cortisol synthesis inhibitor
Indication(s)	Treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative	Treatment of various fungal infections Treatment of Cushing syndrome in adults a	Treatment of Cushing disease in adults for whom pituitary surgery is not an option or has not been curative
Mechanism of action	Inhibits synthesis of cortisol and testosterone	Blocks synthesis of ergosterol resulting in changes to the fungal cell membrane	Inhibits synthesis of cortisol

^aOff-label use in the United States.

Clinical Pharmacology

Levoketoconazole is the 2S,4R enantiomer derived from racemic ketoconazole and is an orally administered cortisol synthesis inhibitor. In vitro, levoketoconazole inhibits key steps in the synthesis of cortisol and testosterone, principally those mediated by CYP11B1 (11β-hydroxylase), CYP11A1 (cholesterol side-chain cleavage enzyme, the first step in conversion of cholesterol to pregnenolone), and CYP17A1 (17α-hydroxylase).^1,2,11

Based on in vitro studies, levoketoconazole is a more potent inhibitor of these key adrenal cortisol synthesis enzymes than its dextroisomer (dextroketoconazole). Levoketoconazole was about twice as potent as ketoconazole in inhibiting these enzymes, suggesting that most of ketoconazole’s cortisol production inhibitory activity in vivo derives from its 2S,4R enantiomer (ie, levoketoconazole).^2,11,12

Pharmacokinetics

Following a single oral dose of levoketoconazole under fasted conditions (regardless of dose), T_max is 1.5 to 2 hours. C_max increases proportionately with dose, while AUC increases greater than dose proportionally over the dose range of 150 to 600 mg. Administration of levoketoconazole with a high-fat meal increased AUC by 30%, had no effect on C_max, and delayed T_max by 2 hours; however, these changes are not considered clinically significant. ¹

The apparent volume of distribution of levoketoconazole is 31 to 41 L; protein binding is high (99.3%). Levoketoconazole accumulates in plasma during multiple dosing. ¹

Studies (in vitro or in vivo) of levoketoconazole metabolism have not been performed. Much of levoketoconazole’s pharmacokinetic data are based on ketoconazole’s pharmacokinetic profile. Levoketoconazole is a strong CYP3A4 inhibitor and an inhibitor of P-gp, OCT2, MATE1, CYP2B6, and CYP2C8 and an inducer of CYP1A2. Racemic ketoconazole is metabolized extensively in the liver to several inactive metabolites. CYP3A4 is the major enzyme involved in the metabolism of ketoconazole. Major identified metabolic pathways include oxidation and degradation of the imidazole and piperazine rings; additionally, oxidative O-dealkylation, and aromatic hydroxylation occur. ¹

Levoketoconazole is eliminated from plasma, with a half-life of 3 to 4 hours after a single dose and 4 to 6 hours after multiple doses. Approximately 13% of a racemic ketoconazole dose is excreted in the urine (2%-4% as unchanged drug); the major route of excretion is through the bile into the intestinal tract, with approximately 57% excreted in the feces. ¹

Population pharmacokinetic modeling data from patients with Cushing syndrome suggest that age and sex have no impact on the pharmacokinetics of levoketoconazole; the impact of race/ethnicity and renal or hepatic impairment have not been determined. ¹

Comparative Efficacy

Indication: Cushing Syndrome

Guidelines

• Guideline: Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline

• Reference: Endocrine Society, 2015 ¹³

• Comments: Treatment goals for Cushing syndrome are normalization of cortisol levels or action at cortisol receptors to eliminate the signs and symptoms of Cushing syndrome and treatment of comorbidities associated with hypercortisolism. Surgical resection of the causal lesion(s) is recommended as first-line treatment in most cases. Second-line therapy should be individualized to each patient; treatment options include repeat transsphenoidal surgery, pharmacotherapy, bilateral adrenalectomy, and radiotherapy. Pharmacotherapy options include steroidogenesis inhibitors (ie, ketoconazole, metyrapone, mitotane, etomidate), pituitary-directed treatments (ie, cabergoline, pasireotide), and glucocorticoid receptor antagonists (ie, mifepristone). Steroidogenesis inhibitors are recommended as second-line treatment after transsphenoidal selective adenomectomy in patients with Cushing disease, either with or without radiation therapy/radiosurgery; as primary treatment of ectopic ACTH secretion in patients with occult or metastatic ectopic ACTH secretion; and as adjunctive treatment to reduce cortisol levels in adrenocortical carcinoma. Although not an approved use in the United States, the guidelines note that ketoconazole is approved by the European Medicines Agency for the treatment of Cushing syndrome. Levoketoconazole was not available at the time the guidelines were developed.

Studies

• Drug: Levoketoconazole

• Reference: Fleseriu et al, 2019 (SONICS trial)^1,12,14,15

• Study Design: Phase 3, nonrandomized, open-label, single-arm, international study

• Study Funding: Strongbridge Biopharma

• Patients: 94 patients (18 years or older) with confirmed diagnosis of persistent, recurrent, or de novo Cushing disease or endogenous Cushing syndrome due to other causes (if not considered to be a candidate for surgery or radiotherapy within 18 months of enrollment). Patients had mean 24-hour urinary free cortisol (UFC) concentration at least 1.5 times the upper limit of normal (ULN) and either abnormal dexamethasone suppression test or elevated late-night salivary cortisol concentrations. Patients who had received radiation therapy were eligible if treatment had occurred at least 4 years previously and no improvement was observed during the previous 6 months; patients who had experienced surgical failure were also eligible if surgery had occurred at least 6 weeks previously. Exclusion criteria included pseudo-Cushing syndrome, cyclic Cushing syndrome, exogenous hypercortisolism, or malignancy-associated hypercortisolism; history of malignancy within 3 years of screening; optic chiasm compression; QT prolongation or abnormal ECG requiring medical intervention; preexisting hepatic disease; ALT or AST greater than 3 times the ULN or total bilirubin greater than 2 times the ULN; persistent, uncontrolled hypertension; poorly controlled diabetes; and hypercortisolism caused by a known inherited syndrome.

• Mean patient age was 43.7 years; 82% were female; 96% were White; 85% had pituitary Cushing syndrome; and mean baseline mean UFC was 4.9 times the ULN. Ninety-four patients were enrolled and received at least 1 dose of study drug (intention-to-treat population), 77 entered the maintenance phase, and 61 completed the maintenance phase.

• Intervention: The study consisted of 3 phases: a dose titration phase (2 -21 weeks to achieve therapeutic dose), a maintenance phase (6 months of treatment at the therapeutic dose), and an extended evaluation phase (6 months of continued treatment). During the dose titration phase, levoketoconazole was initiated at 150 mg orally twice daily and then increased (based on mean UFC) in increments of 150 mg/day no more frequently than every other week up to a maximum dosage of 600 mg twice daily. Patients who achieved a therapeutic dose (defined as dose at which mean UFC at or below the ULN was achieved, or dose of 600 mg twice daily or the maximum tolerated dose reached with clinically meaningful partial response based on clinical judgment) continued to the maintenance phase. During the maintenance phase, the therapeutic dose was kept stable, unless an adjustment was needed to maintain control of hypercortisolism or for safety or tolerability issues.

• Results: Results are reported for the end of the 6-month maintenance phase.

• Primary End Point(s):

  • ● Proportion of patients with normalization of mean UFC at completion of the 6-month maintenance phase without requiring a dose increase at any time during the maintenance phase: 31%; least squares (LS) mean estimate of the proportion of responders was 0.3 (95% CI, 0.21-0.4; P = .0154 vs null hypothesis of ≤0.2).

    • ○ Response rate was 0.48 (95% CI, 0.37-0.59) at month 1, 0.5 (95% CI, 0.39-0.61) at month 2, 0.44 (95% CI, 0.34-0.55) at month 3, 0.35 (95% CI, 0.25-0.46) at month 4, and 0.36 (95% CI, 0.26-0.47) at month 5.

• Secondary End Point(s):

• ● Proportion of patients with mean UFC normalization at month 6 irrespective of a dose increase: 36%; LS mean response rate, 0.36 (95% CI, 0.26-0.46).

  • ○ Of the 55 patients who completed the maintenance phase and had both baseline and end-of-maintenance mean UFC data, 34 (62%) had mean UFC normalization.
• ● Proportion of patients with at least a 50% reduction from baseline in mean UFC or UFC normalization at month 6 irrespective of a dose increase: 46%; LS mean response rate, 0.46 (95% CI, 0.35-0.56).

  • ○ Of the 55 patients who completed the maintenance phase and had both baseline and end-of-maintenance mean UFC data, 43 (78%) had mean UFC normalization.

• ● Change form baseline to month 6 in Cushing syndrome comorbidity biomarkers: Mean improvements in several biomarkers (eg, fasting blood glucose concentration, HbA_1c, low-density lipoprotein cholesterol [LDL-C], total cholesterol, body weight) were observed; however, a reduction in high-density lipoprotein cholesterol and an increase in serum triglyceride levels also occurred.

• ● Change from baseline to month 6 in clinical signs and symptoms of Cushing syndrome: Improvements in clinician-rated acne global score, hirsutism total score (females only), and peripheral edema total score were observed.

• Comments: This study was conducted at 60 sites in 19 countries (15 countries in Europe and Canada, Israel, Turkey, and the United States). Normalization of mean UFC was defined as mean UFC at or below the ULN. This study is referred to as Study 2 in the levoketoconazole prescribing information.

• A subgroup analysis of patients with diabetes mellitus showed mean UFC normalization with levoketoconazole was similar in patients with and without diabetes mellitus; some patients were able to lower the dose of their diabetes medication(s); and improvements were observed in LDL-C, weight, body mass index, and waist circumference.^16,17

• Of the 61 patients who completed the maintenance phase, 60 entered the extended evaluation phase. During the extension phase, no patients experienced an increase in ALT or AST greater than 3 times the ULN, adrenal insufficiency, or QTcF interval of greater than 460 ms; concentration-response modeling showed no evidence of tolerance to mean UFC reduction; and improvements in Cushing syndrome comorbidity biomarkers (eg, fasting blood glucose concentration, HbA_1c, LDL-C, total cholesterol, body weight) observed during the maintenance phase were also observed through month 12. ¹⁸

• Limitations: This was an open-label study without a control group; a direct efficacy comparison between ketoconazole and levoketoconazole was not conducted; and the study discontinuation rate was high (35% of patients discontinued treatment due to adverse reaction[s], lack of efficacy, or other reasons).

• Drug: Levoketoconazole vs Placebo

• Reference: Recorlev prescribing information, 2021 (LOGICS trial)^1,19-21

• Study Design: Phase 3, double-blind, placebo-controlled, randomized withdrawal and rescue/restoration study

• Study Funding: Strongbridge Biopharma

• Patients: 84 patients (18 years or older) with Cushing syndrome and persistent or recurrent disease despite surgery. Patients who were naive to treatment with levoketoconazole as well as patients who received levoketoconazole in the SONICS study were included. Patients enrolled in SONICS were included if they had completed the final study visit and demonstrated maintenance of clinical response on a stable therapeutic dose of levoketoconazole for at least 12 weeks prior to LOGICS study entry. For patients not enrolled in SONICS, inclusion criteria included newly diagnosed, persistent, or recurrent endogenous Cushing syndrome of any etiology (except secondary to malignancy); mean UFC at least 1.5 times the ULN; either abnormal dexamethasone suppression test or elevated late-night salivary cortisol concentrations; and noncandidacy for Cushing syndrome–specific surgery (or agreement to delay surgery until after study completion) or if postsurgical, no remaining significant postoperative outcomes and negligible risk of such outcomes. Exclusion criteria included pseudo-Cushing syndrome; cyclic Cushing syndrome with multiweek periods of apparent spontaneous remission; nonendogenous hypercortisolism; pituitary or adrenal carcinoma; radiotherapy for hypercortisolism within the previous 5 years; treatment with mitotane within the previous 6 months; and clinical or radiological signs of optic chiasm compression.

• Mean patient age was 45 years; 76% were female; mean time since diagnosis was 63 months; 83% had Cushing disease, 10% had adrenal Cushing syndrome, 2% had ectopic ACTH secretion, and 5% had Cushing syndrome of unknown cause; and baseline mean UFC was approximately 6 times the ULN. Of the 84 patients enrolled, 44 entered the randomized withdrawal phase (39 from the dose titration and maintenance phase and 5 directly from the SONICS study); in the randomized withdrawal population, mean age was 44.3 years, 77% were female, 91% were White, mean weight was 83.2 kg, and 86% had Cushing disease.

• Intervention: The study consisted of 3 phases: a dose titration and maintenance phase (14-19 weeks); an 8-week, double-blind, placebo-controlled, randomized withdrawal phase; and an 8-week restoration phase. During the dose titration and maintenance phase, levoketoconazole was initiated at 150 mg orally twice daily in patients naive to levoketoconazole; patients who participated in the SONICS trial could start on a dose higher than 150 mg twice daily. The dose was titrated in 150 mg increments at 2-week intervals to a maximum dose of 600 mg twice daily to achieve mean UFC within the normal range. Patients who achieved a stable therapeutic dose for at least 4 weeks and a normal mean UFC could continue to the randomized withdrawal phase. During the randomized withdrawal phase, patients were randomized 1:1 to either continue levoketoconazole (n = 22) or receive matched placebo (n = 22) for approximately 8 weeks or until early rescue was necessary (ie, for mean UFC greater than 1.5 times the ULN).

• Results:

• Primary End Point(s):

  • ● Proportion of patients with loss of therapeutic response to levoketoconazole during the randomized withdrawal phase: 40.9% with levoketoconazole compared to 95.5% with placebo; treatment difference, −54.5% (95% CI, −75.7% to −27.4%; P < .001).

    • ○ During the randomized withdrawal phase, median time on treatment was 55.5 days (range, 16-62 days) with levoketoconazole and 23 days (range, 16-62 days) with placebo, indicating rapid loss of cortisol control upon levoketoconazole cessation.
    • ○ Most placebo patients (21 of 22) received early rescue therapy due to loss of therapeutic response.
• Secondary End Point(s):

  • ● Proportion of patients with mean UFC normalization (defined as mean UFC at or below the ULN without meeting a requirement for early rescue) at the end of the randomized withdrawal phase: 50% with ketoconazole compared to 4.5% with placebo; treatment difference, 45.5% (95% CI, 19.2%-67.9%; P < .001).

    • ○ n the 39 patients who had normal mean UFC at randomized withdrawal baseline, the proportion was 52.4% with levoketoconazole and 5.6% with placebo; treatment difference, 46.8% (95% CI, 16.5%-70.2%).
  • ● Change in Cushing syndrome comorbidity biomarkers during the randomized withdrawal phase: Mean total cholesterol and LDL-C levels were increased with placebo and slightly decreased with levoketoconazole; mean changes in glycemia markers and high-sensitivity C-reactive protein were not significantly different between treatment groups.

• Comments: Loss of therapeutic response was defined as mean UFC 1.5 times the ULN or higher, mean UFC greater than 40% above baseline if baseline was greater than 1 times the ULN, or meeting another rescue criterion. This study is referred to as Study 1 in the levoketoconazole prescribing information.

• During the titration-maintenance phase, mean change in mean UFC from baseline to last observed value was −172.7 µg/day. At randomized withdrawal baseline, mean UFC was 29.5 µg/day in the levoketoconazole group and 32 µg/day in the placebo group; mean change in mean UFC from randomized withdrawal baseline to end of randomized withdrawal was 50.5 µg/day with levoketoconazole and 164.3 µg/day with placebo (mean treatment difference, −113.8 µg/day; P = .0027).

• Interim results of LOGICS confirmed the safety and efficacy findings of SONICS and established treatment benefit as levoketoconazole specific. Levoketoconazole was generally well tolerated, and no new safety signals were detected. Risks were expected and manageable with appropriate monitoring. ²⁰

• A phase 3, long-term, open-label extension study to evaluate use of levoketoconazole in patients with endogenous Cushing syndrome who completed one or both parent studies or who otherwise qualify for inclusion (as defined in the eligibility criteria) is ongoing, with an estimated study completion date of June 2023. ²²

• Limitations: LOGICS results are only available in the prescribing information and as abstracts of an interim analysis. Results were only assessed in patients who achieved a stable therapeutic dose of levoketoconazole for at least 4 weeks and a normal mean UFC during the titration-maintenance phase.

Contraindications, Warnings, and Precautions

Contraindications

Levoketoconazole is contraindicated in the following situations:

• Patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT greater than 3 times the ULN, recurrent symptomatic cholelithiasis, a history of drug-induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease;

• Patients taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes;

• Patients with prolonged QTcF interval greater than 470 ms at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history);

• Patients taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp; and

• Patients with hypersensitivity to levoketoconazole, ketoconazole, or any component of the levoketoconazole formulation (ie, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, modified corn starch, silicified microcrystalline cellulose, iron oxide red, macrogol/PEG 3350, polyvinyl alcohol partially hydrolyzed, talc, titanium dioxide, ammonium hydroxide, ferrosoferric oxide, isopropyl alcohol, propylene glycol, shellac glaze 45% in ethanol). ¹

Warnings and Precautions

The warnings and precautions associated with levoketoconazole are similar to those for oral ketoconazole.^1,10

Levoketoconazole has a boxed warning regarding the risk of hepatotoxicity and QT prolongation. ¹

Hepatotoxicity, including cases resulting in a fatal outcome or requiring liver transplantation, has been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving levoketoconazole, irrespective of the dosages used or treatment duration. Avoid concomitant use of levoketoconazole with hepatotoxic drugs and advise patients to avoid excessive alcohol consumption during treatment. Liver enzymes and bilirubin should be routinely monitored during treatment. If hepatotoxicity occurs, immediately interrupt levoketoconazole; if liver abnormality significantly above baseline recurs after restarting levoketoconazole, permanently discontinue levoketoconazole (see Dosing for recommendations). ¹ The manufacturer is required to conduct postmarketing pharmacovigilance for all cases of hepatotoxicity reported with levoketoconazole therapy. ²³

Levoketoconazole is associated with dose-related QT interval prolongation. QT interval prolongation may lead to life-threatening ventricular dysrhythmias (eg, torsades de pointes). Levoketoconazole is contraindicated in patients taking other drugs known to cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, and in patients with prolonged QTcF interval greater than 470 ms at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Use levoketoconazole with caution in patients with other risk factors for QT prolongation (eg, congestive heart failure, bradyarrhythmias, uncorrected electrolyte abnormalities) and monitor ECG more frequently. Correct hypokalemia and/or hypomagnesemia prior to initiating treatment with levoketoconazole. ECG and electrolyte monitoring is recommended throughout therapy. ¹

Levoketoconazole lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Hypocortisolism may occur at any time during treatment. In clinical studies of levoketoconazole, the majority of cases of hypocortisolism were managed by reducing the dosage or temporarily interrupting treatment. Monitor 24-hour UFC, morning serum or plasma cortisol, and for signs/symptoms of lowered cortisol levels (eg, nausea, vomiting, fatigue, abdominal pain, appetite loss, dizziness) periodically during treatment. Following discontinuation of levoketoconazole, cortisol suppression may persist beyond the 4- to 6-hour half-life of levoketoconazole. If UFC or morning blood cortisol levels fall below target range, a rapid decrease in cortisol levels occurs, or signs/symptoms of hypocortisolism are reported, decrease the dose or temporarily withhold levoketoconazole (see Dosing for recommendations). ¹

Hypersensitivity reactions were reported in 1% of patients treated with levoketoconazole in clinical trials. Anaphylaxis has been reported after a single oral dose of ketoconazole. Levoketoconazole is contraindicated in patients with hypersensitivity to levoketoconazole or ketoconazole. ¹

Levoketoconazole may lower testosterone levels in males and females. Potential clinical manifestations include gynecomastia, impotence, oligospermia, decreased libido, and mood changes. ¹

There are no adequate and well-controlled studies of levoketoconazole use during pregnancy. No animal reproduction studies have been performed with levoketoconazole; however, levoketoconazole constitutes approximately 70% of the exposure in humans and animals after racemic ketoconazole administration. In animal reproduction studies, embryotoxic effects were observed following oral dosing of racemic ketoconazole. Active Cushing syndrome during pregnancy has been associated with an increased risk of maternal and fetal morbidity and mortality, including gestational diabetes, gestational hypertension, preeclampsia, maternal death, miscarriage, intrauterine fetal demise, preterm birth, and neonatal death. Advise pregnant patients of the potential risk to a fetus and consider whether the benefits of treatment with levoketoconazole outweigh the risks. ¹

There are no data regarding the presence of levoketoconazole in human milk, or its effects on breastfeeding infants or milk production. Ketoconazole is present in breast milk. Because of the potential for serious adverse reactions in a breastfeeding infant, including liver toxicity, the manufacturer recommends that patients be advised not to breastfeed during treatment with levoketoconazole and for 1 day after the final dose. ¹

Levoketoconazole may lower testosterone levels and impair male and female fertility. ¹

Safety and effectiveness of levoketoconazole have not been established in pediatric patients. ¹ Because of levoketoconazole’s orphan drug designation, the manufacturer is not required to conduct pediatric studies. ²³

Adverse Reactions

The most common adverse reactions (incidence greater than 20%) with levoketoconazole are erythema, hemorrhage/contusion, fatigue, headache, nausea/vomiting, abdominal pain/dyspepsia, hypokalemia, arthritis, upper respiratory tract infection, hepatic injury, myalgia, abnormal uterine bleeding, arrhythmia, back pain, insomnia/sleep disturbances, peripheral edema, and systemic hypertension. ¹ Adverse reactions (excluding hepatic injury) occurring at a frequency of 10% or higher in the SONICS and LOGICS clinical trials are summarized in Tables 2 and 3. ¹

Table 2.

Adverse Reactions, Excluding Hepatic Injury, With Levoketoconazole (Incidence ≥10%) in Patients With Cushing Syndrome in the LOGICS Trial. ¹

Adverse reaction	N = 84 (%)
Nausea/vomiting	30
Hypokalemia	29
Hypertension	24
Hemorrhage/contusion	23
Headache	21
Abnormal uterine bleeding	20
Arrhythmia	19
Fatigue	18
Upper respiratory infection	18
Abdominal pain/dyspepsia	15
Dizziness	15
Diarrhea	15
Decreased appetite	13
Dry mouth	11
Dry skin	11
Adrenal insufficiency	11

Table 3.

Adverse Reactions, Excluding Hepatic Injury, With Levoketoconazole (Incidence ≥10%) in Patients With Cushing Syndrome in the SONICS Trial. ¹

Adverse event	N = 94 (%)
Erythema	43
Hemorrhage/contusion	40
Fatigue	39
Headache	38
Nausea/vomiting	37
Abdominal pain/dyspepsia	33
Arthritis	28
Upper respiratory infection	28
Myalgia	26
Abnormal uterine bleeding	24
Arrhythmia	24
Back pain	22
Insomnia/sleep disturbances	22
Peripheral edema	20
Systemic hypertension	20
Diarrhea	19
Presyncope/syncope	18
Rash	17
Urinary tract infection	16
Hypokalemia	15
Pruritus	15
Disturbance in attention	14
Irritability	14
Depression	12
Dry skin	12
Alopecia	11

In 5 studies evaluating use of ketoconazole for the treatment of Cushing disease (N = 310), adverse reactions reported at an incidence of 10% or greater in at least 1 study included increased liver enzymes, GI disturbances, adrenal insufficiency, hepatotoxicity, and fatigue. ²⁴

In LOGICS and SONICS, 27% of patients experienced at least 1 liver-related adverse reaction, with the majority being liver enzyme elevations (20%); other liver-related adverse events included hepatic pain (4%), drug-induced liver injury (2%), liver disorders (2%), and hepatic steatosis (1%). Elevations in AST or ALT occurred in 45% of patients; median time to event was 73 days (range, 1-334 days). ¹

In LOGICS and SONICS, 19% (15 of 80) and 13% (12 of 94) of patients, respectively, discontinued the study due to adverse effects.^12,20

Drug Interactions

Levoketoconazole is a strong CYP3A4 inhibitor. It is also an inhibitor of P-gp, OCT2, and MATE1 in vivo and CP2B6 and CYP2C8 in vitro. Concomitant use of levoketoconazole with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions to these drugs. ¹

In addition, levoketoconazole is associated with dose-related QT prolongation and may also elevate plasma concentrations of other drugs that prolong the QT interval. Concomitant use of levoketoconazole with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes (eg, bosutinib, cisapride, clarithromycin, cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat [in patients who are poor or intermediate CYP2D6 metabolizers and in patients taking strong or moderate CYP2D6 inhibitors], ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, ranolazine) is contraindicated. ¹

Use of levoketoconazole with sensitive CYP3A4 or CYP3A4 and P-gp substrates (eg, alfentanil, avanafil, buspirone, conivaptan, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, vardenafil) increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions; concomitant use is contraindicated or not recommended (refer to the prescribing information for the substrate drug). ¹

Use of levoketoconazole with strong CYP3A4 inhibitors (eg, ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir, mifepristone) may increase plasma concentrations of levoketoconazole and the risk of adverse reactions; coadministration is not recommended. Avoid use of strong CYP3A4 inhibitors within 2 weeks of starting levoketoconazole and during treatment. ¹

Strong CYP3A4 inducers (eg, isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine, mitotane) may decrease plasma concentrations of levoketoconazole and reduce its efficacy; coadministration is not recommended. Avoid use of strong CYP3A4 inducers within 2 weeks prior to starting levoketoconazole and during treatment. ¹

Coadministration of levoketoconazole with atorvastatin (a CYP3A4 substrate) increases plasma concentrations of atorvastatin and may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis; use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg/day. ¹

Coadministration of levoketoconazole with metformin (an OCT2 and MATE substrate) increases plasma concentrations of metformin and may increase the risk of metformin-related adverse reactions. During levoketoconazole dosage titration, monitor glucose levels, kidney function, and vitamin B₁₂ levels and adjust the metformin dose as needed. Levoketoconazole may also increase plasma concentrations of other OCT2 and MATE substrates. ¹

Gastric acid neutralizers (eg, aluminum hydroxide) impair absorption of levoketoconazole. Administer gastric acid neutralizers at least 2 hours after levoketoconazole. Gastric acid suppressors (eg, H₂ receptor antagonists, proton pump inhibitors) or sucralfate impair levoketoconazole absorption; avoid concomitant use. ¹

When used with alcohol, cases of a disulfiram-like reaction have been reported with ketoconazole; symptoms completely resolved within a few hours. ¹

Recommended Monitoring

Obtain cortisol levels from at least two 24-hour UFC samples at baseline and every 2 to 3 weeks until an adequate clinical response is achieved, then at least every 1 to 2 months or as indicated. Monitor morning serum or plasma cortisol as needed during therapy and periodically assess patients for signs/symptoms of hypocortisolism (eg, abdominal pain, loss of appetite, dizziness, electrolyte abnormalities, fatigue, hypoglycemia, hypotension, nausea, vomiting). ¹

Evaluate liver enzymes (eg, ALT, AST) and bilirubin prior to the start of therapy and monitor weekly for at least 6 weeks after starting levoketoconazole, every 2 weeks for the next 6 weeks, monthly for 3 months, then as clinically indicated. After any dose interruption or dose increase, monitor on a weekly basis until a stable dosage is achieved. ¹

Perform an ECG prior to starting therapy and before each dose increase. After a stable dose is established, monitor routinely for an effect on QT interval. Evaluate serum potassium and magnesium levels at baseline and monitor periodically throughout treatment. ¹

Dosing

Prior to initiating levoketoconazole therapy, obtain an ECG and liver tests (ALT, AST, total bilirubin) and correct hypokalemia and hypomagnesemia. The recommended initial levoketoconazole dosage is 150 mg orally twice daily (with or without food). The dosage is then titrated by 150 mg/day no more frequently than every 2 to 3 weeks based on 24-hour UFC levels and patient tolerability. The maximum recommended dosage is 1.2 g/day, administered as 600 mg twice daily. If necessary, the dosage may be reduced to 150 mg once daily for tolerability. Once the maintenance dose is achieved, 24-hour UFC levels should be assessed every 1 to 2 months or as clinically indicated. If 24-hour UFC levels remain above the ULN after treatment with the maximum recommended dosage of 1.2 g/day, or the patient cannot tolerate treatment with levoketoconazole, consider discontinuing levoketoconazole and switching the patient to another therapy. ¹

If a dose is missed, advise patient to take the next dose at the regularly scheduled time. ¹

Hepatotoxicity: Use of levoketoconazole is contraindicated in patients with baseline ALT/AST greater than 3 times the ULN or with any of the following: cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, extensive metastatic liver disease, or history of drug-induced liver injury (requiring discontinuation of treatment) due to ketoconazole or any azole antifungal therapy. For patients with ALT/AST above normal but less than or equal to 3 times the ULN, no dosage adjustment is required; consider risks and benefits before starting therapy in these patients. See Table 4 for dosing recommendations for hepatotoxicity during treatment with levoketoconazole. ¹

Table 4.

Levoketoconazole Dosage Modifications for Hepatotoxicity. ¹

ALT or AST	Total bilirubin	Recommendation
≥5×ULN	Any value	Permanently discontinue levoketoconazole.
≥3×ULN	>2×ULN	Permanently discontinue levoketoconazole.
3 to <5×ULN	≤2×ULN	Temporarily discontinue levoketoconazole and monitor liver tests every 3 days until stable and then at least every 7-10 days until values return to baseline. Once liver tests normalize and other possible contributing factors have been addressed, levoketoconazole may be restarted at a lower dosage and titrated more slowly. Prior to considering a dosage increase, monitor liver tests weekly for 1 month and then routinely thereafter. If a significant liver test abnormality recurs after restarting levoketoconazole, permanently discontinue levoketoconazole.
>ULN to <3×ULN	Any value	Monitor liver tests at least every 7-10 days and consider temporary discontinuation of levoketoconazole. If levoketoconazole is discontinued, restart at a lower dosage and titrate more slowly once liver tests return to baseline and other possible contributing factors have been addressed. Prior to considering a dosage increase, monitor liver tests weekly for 1 month to ensure stability of liver tests.

QT prolongation: Temporarily discontinue levoketoconazole if QTcF interval is greater than 500 ms. After correction of other possible contributing factors (eg, hypokalemia, hypomagnesemia, use of concomitant QT prolonging dugs), levoketoconazole may be restarted at a lower dosage when QTcF interval returns to 500 ms or less. If QT interval prolongation recurs, permanently discontinue levoketoconazole. ¹

Adrenal insufficiency: Decrease the dose or temporarily interrupt levoketoconazole if UFC or morning serum or plasma cortisol levels drop below target range, there is a rapid decrease in cortisol levels, or if signs or symptoms of hypocortisolism/adrenal insufficiency occur. If morning serum or plasma cortisol levels are below target range and signs and/or symptoms of adrenal insufficiency or hypocortisolism are present, stop levoketoconazole and administer exogenous glucocorticoid replacement therapy. Levoketoconazole may be restarted at a lower dose when cortisol levels are within target range and signs and/or symptoms of hypocortisolism have resolved. If reduced dose is well tolerated, the dose may be titrated to the previous dose as needed. ¹

Product Availability and Storage

Levoketoconazole was approved by the FDA on December 30, 2021. ²³

Levoketoconazole is available as 150 mg tablets in bottles of 50. Levoketoconazole should be stored at 20°C to 25°C (68°F-77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). ¹

Drug Safety/REMS

No REMS is required for levoketoconazole. ²³

Conclusion

Levoketoconazole, a cortisol synthesis inhibitor, is FDA approved for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative. Few pharmacotherapy options are available for the treatment of Cushing syndrome and data are limited. Ketoconazole is approved for the treatment of endogenous Cushing syndrome in Europe but is used off label for this indication in the United States. Use of ketoconazole is limited by side effects (eg, hepatotoxicity) and numerous drug interactions. Studies suggest that levoketoconazole, an enantiomer of ketoconazole, may inhibit cortisol more potently than ketoconazole and have a more favorable side effect profile and lower risk for hepatotoxicity. Levoketoconazole offers a useful therapeutic option for the medical treatment of Cushing syndrome.