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MyDeficiencies

Levoketoconazole

steroidogenesis inhibitor (enzyme inhibitor)

Also sold as Recorlev.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Levoketoconazole has real classical depletion machinery, and one signal clears the strictest bar in this series to date. It is extensively hepatically metabolized, is itself a strong CYP3A4 inhibitor in vivo (with in vitro inhibition of CYP2B6/CYP2C8, in vitro induction of CYP1A2, and in vivo inhibition of the P-gp, OCT2, and MATE1 transporters), and is 99.3% protein-bound with a short 3 to 6 hour half-life. Its own labeled mechanism, direct inhibition of CYP11B1 (11-beta-hydroxylase), CYP11A1, and CYP17A1, blocks cortisol synthesis at multiple steps, more broadly than metyrapone's single-enzyme action, and forces the same upstream consequence: loss of cortisol feedback raises ACTH, driving overproduction of 11-deoxycorticosterone (DOC), a mineralocorticoid-receptor agonist. Unlike metyrapone, whose potassium signal in this project's earlier review was capped at orange for lack of a quantified figure, levoketoconazole's two independent pivotal registration trials each report hypokalemia directly and by name: 29% in the single-arm SONICS study and 15% in the randomized-withdrawal LOGICS study, both with levoketoconazole in the cohort, both consistent in direction, and both grounded in the same named, drug-specific mechanism. Potassium is accordingly graded red, the first red grade in this reviewer's pass through the adrenal-steroidogenesis-inhibitor class. Sodium and fluid retention, the mirror-image consequence of the same DOC pathway, is graded orange on quantified hypertension (24% and 20% across the two trials) and edema (20%) outcomes, though serum sodium itself was never directly reported. A separate, real but indirect signal exists for vitamin B12: levoketoconazole's confirmed in vivo inhibition of the OCT2/MATE1 transporters raises metformin exposure by 220%, and the label directs vitamin B12 monitoring in that bounded, metformin-co-prescribed subgroup, graded orange.

steroidogenesis inhibitor (enzyme inhibitor) · ATC H02CA04 · also sold as Recorlev · reviewed 2026-09-28. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Levoketoconazole in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Potassium, mineralocorticoid-driven wasting, quantified in both pivotal trials

Red — Severe

See study details

Levoketoconazole causes real, quantified hypokalemia in a substantial minority of patients, driven by its own core steroidogenesis-blocking mechanism, confirmed independently in both pivotal registration trials.

Full detail, limits and 4 references

What the grade means here: Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence. red

Limits on what this shows

  • Key negative/null findings: Neither trial's summary data, as retrieved through the label and the systematic review, reports hospitalization for severe hypokalemia; the label frames the risk as manageable through baseline correction and periodic monitoring rather than as an unmanageable one.
  • At-risk subgroups: Patients not pre-corrected for baseline hypokalemia, those on higher doses achieving more complete steroidogenesis blockade, and patients also taking other potassium-wasting agents (not itself studied in this program).
  • Counter-evidence on record: None identified contradicting the direction or presence of the effect. The two trials differ in magnitude (29% vs 15%), a difference consistent with Study 2's randomized-withdrawal design and different exposure characteristics rather than a genuine contradiction; this is disclosed rather than smoothed over.

Regulatory status

Label requires correcting hypokalemia before starting RECORLEV and monitoring blood potassium periodically during treatment; hypokalemia is listed among the most common (≥20% overall) adverse reactions.

Population evidence

Study 1 (SONICS, phase 3, single-arm, open-label; Fleseriu et al 2019, Lancet Diabetes & Endocrinology, DOI 10.1016/S2213-8587(19)30313-4): hypokalemia in 24 of 84 patients (29%). Study 2 (LOGICS, phase 3, double-blind, placebo-controlled, randomized-withdrawal; Pivonello et al 2022, Pituitary, PMID 36085339): hypokalemia in 14 of 94 patients (15%). Both figures are drawn from the FDA label's adverse-reaction tables for these two independent, levoketoconazole-in-cohort pivotal trials. A drug-specific systematic review of the levoketoconazole clinical program (Patra et al 2024, Indian J Endocrinol Metab, PMID 39371660) corroborates hypokalemia as a leading adverse event across both studies.

Mechanism

Named and drug-specific: levoketoconazole's own label states its mechanism as direct inhibition of CYP11B1 (11-beta-hydroxylase), plus CYP11A1 and CYP17A1. Blocking CYP11B1 prevents conversion of 11-deoxycorticosterone (DOC) to corticosterone; loss of cortisol feedback raises ACTH, which drives further precursor overproduction. DOC is a mineralocorticoid-receptor agonist and causes renal potassium wasting independent of aldosterone. This exact steroid-precursor accumulation was measured directly with the parent racemic compound, ketoconazole, in both healthy subjects and Cushing's syndrome patients (Engelhardt et al 1984, Acta Endocrinologica, DOI 10.1530/acta.0.107s115-a), a Tier C class-level confirmation of the mechanism (ketoconazole, not the pure levo-enantiomer, was the tested compound in that study).

Counter-evidence held on record

This is a mineralocorticoid-mediated wasting effect of the drug's own core mechanism, not a dietary potassium deficiency, and it is not a basis for pre-emptive potassium supplementation. Because RECORLEV also carries a boxed QT-prolongation warning for which hypokalemia is a potentiating risk factor, any potassium repletion must be clinician-directed and monitored; overcorrection carries its own arrhythmia risk. No potassium dose is recommended anywhere in this dossier.

Sodium, fluid-retention direction from the same DOC pathway, not directly measured

Orange — Moderate

See study details

The mirror image of the potassium finding: quantified hypertension and edema in both trials are consistent with DOC-driven mineralocorticoid excess promoting sodium and fluid retention, though serum sodium itself was never directly reported.

Full detail and limits

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. orange

Limits on what this shows

  • Key negative/null findings: None specific to sodium; hypertension and edema are clinical outcomes, not direct sodium measurements, and are named here as outcomes per Hard Rule 2, not conflated with a laboratory sodium value.
  • At-risk subgroups: Same as the Potassium entry; also patients with pre-existing hypertension or heart failure given the added fluid-retention risk.
  • Counter-evidence on record: None identified.

Regulatory status

Systemic hypertension and peripheral edema both appear among the label's common (≥20% overall) adverse reactions; the label requires monitoring "fluid/electrolyte balance."

Population evidence

Study 1 (SONICS): systemic hypertension in 20 of 84 patients (24%); peripheral edema not separately listed. Study 2 (LOGICS): systemic hypertension in 19 of 94 patients (20%) and peripheral edema in 19 of 94 patients (20%). No serum sodium or hypernatremia figure was reported in either trial's adverse-reaction tables or located elsewhere in the literature searched.

Mechanism

Named, shared with the Potassium entry: DOC is a mineralocorticoid-receptor agonist; renal mineralocorticoid excess drives distal-tubule sodium reabsorption in exchange for potassium/hydrogen excretion. See Overlap map.

Counter-evidence held on record

This is a retention/excess risk inferred from clinical outcomes consistent with the drug's own mineralocorticoid-excess mechanism, not a measured sodium value, and it is never a basis for increasing sodium intake. Blood pressure and edema should be monitored by the prescribing clinician; no diuretic or dietary sodium change should be self-directed.

Vitamin B12, indirect, bounded to concomitant metformin use

Orange — Moderate

See study details

Levoketoconazole does not affect B12 directly; it potently inhibits the OCT2/MATE1 transporters that clear metformin, raising metformin exposure 220%, and the label directs B12 monitoring in that specific co-prescribed population because metformin itself is a well-established cause of B12 depletion.

Full detail, limits and 1 references

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. orange

Limits on what this shows

  • Key negative/null findings: No source located quantifies how much the 220% metformin AUC increase further elevates metformin's own B12-lowering effect beyond metformin's established baseline risk.
  • At-risk subgroups: Patients on RECORLEV who are also taking metformin, particularly at higher metformin doses or longer treatment duration, matching metformin's own established B12-depletion risk factors.
  • Counter-evidence on record: None found.

Regulatory status

Label drug-interaction table: concomitant metformin AUC increased 220% (90% CI 203-239%); explicit instruction to "monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust dosage as needed."

Population evidence

Dedicated pharmacokinetic drug-interaction study, NCT03880825 ("Drug Interaction Study of Levoketoconazole and Metformin," 2019), cited directly in the label's interaction table; levoketoconazole was in the studied cohort. Tier A.

Mechanism

Named, and direction-checked per Hard Rule 4: this is not levoketoconazole directly antagonizing B12. It is a transporter-mediated drug-drug interaction (in vivo inhibition of renal OCT2/MATE1, confirmed for levoketoconazole itself) that raises exposure to a second drug, metformin, which has its own separately documented mechanism for lowering B12 (reduced intrinsic-factor-mediated ileal absorption). The B12 risk is metformin's own effect, potentiated by levoketoconazole's pharmacokinetic interaction, not a direct levoketoconazole-B12 mechanism.

Counter-evidence held on record

This is not a direct levoketoconazole-B12 mechanism; it is real but bounded to patients also taking metformin, where the label's own instruction to monitor B12 should be followed per metformin's prescribing information. It does not imply that levoketoconazole alone, without metformin, affects B12 status. No B12 dose is recommended by this entry.

Magnesium, label-mandated monitoring, no quantified drug-induced deficit found

Yellow — Low

See study details

RECORLEV requires correcting hypomagnesemia before starting and monitoring magnesium periodically, but this is because low magnesium potentiates the drug's own labeled QT-prolongation risk, not because levoketoconazole has been shown to cause magnesium loss.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: The absence of any quantified hypomagnesemia adverse-event rate, in the same tables that report hypokalemia precisely, is itself an informative negative finding and is recorded as such.
  • At-risk subgroups: Not established for drug-induced loss; patients with any cause of baseline hypomagnesemia are at higher risk from the drug's QT effect, which is the documented concern.
  • Counter-evidence on record: The absence of a quantified magnesium adverse-event rate alongside a precisely quantified potassium rate in the same tables argues against a comparable depletion effect.

Regulatory status

"Correct hypokalemia and hypomagnesemia prior to starting RECORLEV" (Section 2.1); "Monitor blood potassium and magnesium levels periodically during treatment" (Section 2.3); the same instruction is repeated under the QT boxed-warning section (5.2).

Population evidence

No adverse-event table in the label lists "hypomagnesemia" with an incidence percentage (searched specifically; absent from Tables 2 and 3, which do report hypokalemia precisely). No drug-specific magnesium-wasting study, for levoketoconazole or racemic ketoconazole, was located in the literature searched.

Mechanism

Not established as a levoketoconazole depletion mechanism. Unlike potassium, renal magnesium wasting is not a typical feature of mineralocorticoid excess; DOC/aldosterone pathways act on the distal nephron's sodium/potassium exchange, while magnesium reabsorption occurs mainly in the thick ascending limb. The monitoring requirement instead reflects the reverse relationship named in Hard Rule 4: hypomagnesemia is a risk factor that worsens the drug's own labeled QT-prolongation hazard, so the label requires correcting it as a safety precondition, not because RECORLEV depletes magnesium.

Counter-evidence held on record

Graded yellow as a context flag, not a depletion claim. Do not read the label's monitoring requirement as evidence that levoketoconazole lowers magnesium; it reflects that low magnesium is dangerous in combination with this drug's own QT-prolonging effect. No magnesium supplementation dose is implied by this entry.

Vitamin D, mechanistic, via CYP3A4/CYP27B1, direction genuinely mixed

Yellow — Low

See study details

Levoketoconazole is a confirmed strong CYP3A4 inhibitor, and CYP3A4 is a major human vitamin D 25-hydroxylase; the parent compound, ketoconazole, has independent case-report evidence of therapeutic use suppressing excess active vitamin D, but a separate ketoconazole finding runs the opposite direction, and no study has directly measured vitamin D status in levoketoconazole-treated patients.

Full detail, limits and 3 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: No levoketoconazole-specific or ketoconazole-specific study directly measuring serum 25(OH)D or 1,25(OH)2D in Cushing's syndrome patients was located.
  • At-risk subgroups: Not established.
  • Counter-evidence on record: The Peehl 2001 finding is itself a counter-direction data point against a simple "levoketoconazole lowers vitamin D" narrative, and is reported here rather than omitted.

Regulatory status

Label confirms levoketoconazole is a "strong CYP3A4 inhibitor in vivo" (Section 12.3), drug-specific, Tier A. Vitamin D is not otherwise mentioned anywhere in the label; searched specifically and confirmed absent.

Population evidence

Tier C/B mechanistic references, none with levoketoconazole in the cohort. Gupta et al 2004 (J Bone Miner Res, PMID 15005856) identified CYP3A4 as the human hepatic microsomal enzyme with the highest vitamin D 25-hydroxylase activity among 16 recombinant enzymes screened, with activity "inhibited by recognized CYP3A4 inhibitors"; the retrievable abstract did not name ketoconazole specifically as the inhibitor tested, a limitation disclosed here rather than assumed. A pediatric case report (Nguyen et al 2010, J Pediatr, PMID 20394945, "Infantile Hypercalcemia and Hypercalciuria... Response to Ketoconazole Treatment") documents ketoconazole used specifically to treat vitamin D-mediated hypercalcemia; full abstract text could not be retrieved (no open-access copy found via Unpaywall, publisher paywalled), so this is cited at the level confirmed by its title and indexing only. Running the opposite direction, Peehl et al 2001 (PMID 11502466) describes ketoconazole potentiating, not blunting, vitamin D analogue activity in prostate cancer cells via inhibition of CYP24A1, the vitamin D catabolic enzyme, which would prolong rather than shorten active vitamin D signaling in that tissue context.

Mechanism

Named at the enzyme-family level but directionally unresolved: broad CYP inhibition could plausibly blunt 25-hydroxylation (via CYP3A4) and, by analogy to the parent compound's therapeutic use in hypercalcemia, blunt 1-alpha-hydroxylation of the active hormone (via CYP27B1); the same broad CYP inhibition could instead prolong active vitamin D signaling by blocking its catabolic clearance (via CYP24A1). Both directions rest on the same class of enzyme inhibition; which dominates in a given tissue or patient is not established.

Counter-evidence held on record

This is mechanistic, class-level plausibility with a genuinely unresolved direction, not a demonstrated vitamin D deficiency (or excess) in levoketoconazole-treated patients. No vitamin D dose is recommended by this entry; if a prescriber identifies low vitamin D during routine monitoring, standard, upper-limit-bounded repletion guidance applies independent of this drug.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden, class-level

Yellow — Low

See study details

In isolated mouse liver mitochondria and human HepG2 hepatocytes, the parent racemic compound ketoconazole impaired mitochondrial membrane potential and complex I activity at cytotoxic concentrations, a real mechanistic finding for the drug class but not tested with levoketoconazole itself.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: Voriconazole and fluconazole, other azole antifungals, showed minimal or no cytotoxicity in the same assay system, indicating the mitochondrial effect is not a universal azole-class property but appears concentrated in ketoconazole and posaconazole.
  • At-risk subgroups: The study authors note "preexisting mitochondrial dysfunction" as a plausible susceptibility factor, relevant to RECORLEV's own hepatic-impairment contraindications.
  • Counter-evidence on record: None found specific to levoketoconazole; no in vitro study using the pure levo-enantiomer was located despite a genuine search.

Regulatory status

Not addressed in mitochondrial-specific language in the RECORLEV label; the label's hepatotoxicity boxed warning (13% of patients with peak ALT or AST >3× ULN) is the clinical correlate.

Population evidence

Haegler, Joerin, Krähenbühl, Bouitbir 2017 (Toxicological Sciences 157(1):183-195, PMID 28329820): in isolated mouse liver mitochondria, ketoconazole "impaired membrane potential and complex I activity"; in HepG2 cells, ketoconazole was cytotoxic starting at 20-50 µM, with toxicity onset at 100 µM in HepaRG cells; posaconazole showed comparable effects, while voriconazole and fluconazole showed minimal or no cytotoxicity. Tier C for levoketoconazole (ketoconazole, the racemic compound, was tested, not the pure levo-enantiomer).

Mechanism

Named: direct impairment of electron transport chain complex I activity and mitochondrial membrane potential, offered by the study's authors as a plausible explanation for ketoconazole's clinical hepatotoxicity signal.

Counter-evidence held on record

Class-level, in vitro, cytotoxic-concentration evidence about the parent racemic drug, not a demonstrated systemic mitochondrial-nutrient (for example CoQ10 or B-vitamin cofactor) deficiency in RECORLEV-treated patients, and no supplement is implied. Presented as the most directly relevant mechanistic context available for RECORLEV's own labeled hepatotoxicity signal.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress, same source, superoxide accumulation in hepatocytes

Yellow — Low

See study details

The same ketoconazole in vitro hepatotoxicity study found superoxide accumulation preceding cell death in human HepG2 cells, a class-level oxidative-stress signal tied to the drug's mitochondrial complex I effect, not tested with levoketoconazole itself.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: Voriconazole and fluconazole did not reproduce this effect at comparable concentrations in the same study, again indicating this is not a universal azole property.
  • At-risk subgroups: Same as the Mitochondrial burden entry.
  • Counter-evidence on record: None found for levoketoconazole specifically.

Regulatory status

Not addressed in the label.

Population evidence

Haegler et al 2017 (PMID 28329820, same study as the Mitochondrial burden entry): ketoconazole exposure in HepG2 cells produced "reduced ATP production and superoxide accumulation, ultimately leading to cell death," at concentrations starting 20-50 µM. Tier C for levoketoconazole.

Mechanism

Named: complex I impairment is a well-established source of electron leak and superoxide generation; the study frames the oxidative signal as downstream of the mitochondrial complex I effect described in the Mitochondrial burden entry. See Overlap map.

Counter-evidence held on record

In vitro, cytotoxic-concentration, class-level evidence only. It does not establish systemic oxidative stress in RECORLEV-treated patients and is not a basis for antioxidant supplementation.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper, retention-direction mechanistic signal via cholestatic-pattern hepatotoxicity, not depletion

Yellow — Low

See study details

RECORLEV's own postmarketing safety data include cholestatic hepatitis and cirrhosis among reported hepatobiliary disorders, and copper is excreted almost entirely via bile; cholestatic liver injury is an established cause of copper retention, not loss, though no levoketoconazole-specific copper measurement exists and the drug's typical hepatotoxicity is usually reversible, unlike the chronic cholestatic disease studied in the supporting mechanism reference.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: A separate literature channel located only synthetic coordination-chemistry papers pairing ketoconazole with copper(II) or copper(I) as a metal ligand (for example, novel anticancer or antitrypanosomal ketoconazole-copper complexes synthesized in the laboratory). These describe ketoconazole's nitrogen atoms binding copper ions in a test tube to create new chemical entities; they do not measure or imply anything about copper status in a person taking the drug, and are explicitly not used to support this entry. The label's quantified hepatotoxicity monitoring data (13% peak ALT/AST >3× ULN) do not specify what fraction, if any, is cholestatic rather than hepatocellular, so the size of the at-risk subgroup for this mechanism is unknown.
  • At-risk subgroups: Not established for levoketoconazole specifically. By analogy to the supporting mechanism, only patients who develop the less common cholestatic-pattern (rather than hepatocellular-pattern) hepatotoxicity, and only if that injury were sustained rather than promptly identified and reversed by the label's own mandatory monitoring and dose-modification schedule, would be plausibly at risk.
  • Counter-evidence on record: RECORLEV's hepatotoxicity monitoring protocol (Section 2.1-2.4) is specifically designed to detect and reverse liver injury early through frequent ALT/AST/bilirubin checks and mandatory dose reduction or discontinuation, which argues against the sustained, years-long cholestatic exposure that produced measurable copper retention in the Deering 1977 primary-biliary-cirrhosis cohort. No levoketoconazole- or ketoconazole-specific copper data exists to confirm or refute the mechanism directly.

Regulatory status

Label Section 6.2 (Postmarketing Experience) lists, under Hepatobiliary Disorders: "serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death." Tier A, drug-specific, but postmarketing spontaneous-report data with no denominator or incidence rate. Copper itself is never mentioned anywhere in the label, confirmed by a full-text search of the current label; searched specifically and confirmed absent.

Population evidence

No study measuring copper, ceruloplasmin, or hepatic copper content in levoketoconazole- or ketoconazole-treated patients was located after a renewed multi-channel search in this revision (Crossref, PubMed search-listing pages, multiple phrasings). The supporting mechanism comes from an unrelated condition: Deering, Dickson, Fleming, Geall, McCall, Baggenstoss 1977 (Gastroenterology 72(6):1208-1212, DOI 10.1016/s0016-5085(77)80012-7) directly measured elevated hepatic copper retention in patients with primary biliary cirrhosis, a chronic cholestatic liver disease, and used D-penicillamine to mobilize it. Tier C for levoketoconazole: neither levoketoconazole nor ketoconazole was in that study's cohort, and primary biliary cirrhosis is a distinct, chronic, structural bile-duct disease, not the same entity as RECORLEV's typically reversible, dose-related hepatotoxicity.

Mechanism

Named but two steps removed from levoketoconazole itself: copper's principal excretion route in humans is biliary; cholestasis or impaired bile flow is an established cause of hepatic copper retention (Deering 1977; also the basis of copper accumulation in Wilson's disease, a genetic biliary-copper-transport defect). RECORLEV's own labeled postmarketing hepatobiliary disorders include a cholestatic pattern of injury (hepatitis cholestatic, cirrhosis) alongside its better-characterized hepatocellular pattern (ALT/AST elevation, the basis of the dosing-modification and monitoring rules in Sections 2.1-2.4). Where the cholestatic pattern occurs, copper retention is mechanistically plausible; the label does not state this connection, and it is constructed here from two independently sourced facts rather than found stated together in any single source.

Counter-evidence held on record

This is a retention/excess-direction mechanistic hypothesis, not a demonstrated copper deficiency or excess in RECORLEV-treated patients, and it is not a basis for copper supplementation, which would be the wrong direction of concern if the mechanism is real. It rests on combining a drug-specific but unquantified postmarketing safety signal with an unrelated chronic liver disease's copper physiology, disclosed explicitly rather than presented as directly demonstrated. Any copper-related monitoring should follow a clinician's assessment of a patient's actual liver injury pattern, not this entry.

Iron

Not graded — disclosed evidence gap

See study details

No biological evidence, at any tier, drug-specific or class-level, and no circulating consumer claim, was found linking levoketoconazole or ketoconazole to iron status, even after a renewed search that explicitly tested whether the mechanism supporting the Copper entry above could transfer to iron.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Both conditions for UNGRADED are met after a full renewed search in this revision, not only the original pass. Crossref searches ("ketoconazole iron chelator siderophore," "ketoconazole iron absorption ferritin") returned only unrelated iron-chelation/siderophore chemistry and general ferritin-biology papers with no drug mention; PubMed search-listing pages for ketoconazole plus anemia, erythropoiesis, and hemoglobin returned only unrelated erythropoietin and malaria-anemia papers, none involving ketoconazole. The mechanistic angle used to upgrade the Copper entry in this revision, cholestasis-driven trace-element retention, was explicitly considered for iron and does not transfer: unlike copper, iron is not principally excreted via bile (physiological iron loss is dominated by desquamation and blood loss, not biliary excretion), so impaired bile flow does not plausibly cause iron retention or loss the same way. No consumer claim linking Recorlev/levoketoconazole to iron status was located.

Search channels tried

Crossref works API (multiple phrasings across the original review and this revision), PubMed search-listing pages, DailyMed full-text label search (confirmed no nutrient-relevant mention of iron anywhere in the label; the only "iron" hit is the inert iron oxide red pigment in the tablet's film coating, Section 11, Description). Europe PMC's REST API and the Semantic Scholar API were retried multiple times, spaced out, in this revision and again returned persistent HTTP 403 gateway-level connection rejections on every attempt (confirmed against the proxy's own connection log); they remain unusable. WebSearch was unavailable this session as well, its budget already exhausted before this revision began. This is now a second consecutive genuine multi-channel attempt with the same result; a future revision should re-try Europe PMC and Semantic Scholar specifically once gateway access to those hosts is restored.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Not graded — disclosed evidence gap

See study details

No compositional or functional gut-microbiome study, drug-specific or class-level, and no circulating consumer claim, was found for levoketoconazole or ketoconazole; a plausible antifungal-mycobiome mechanism was considered but could not be substantiated.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Both conditions for UNGRADED are met, after genuine consideration of a specific candidate mechanism rather than a bare null search. Searches for ketoconazole and bacterial gut microbiota/microbiome (Crossref, PubMed) returned zero relevant results. A search for oral azole antifungals and gut fungal colonization/mycobiome (Crossref: "oral azole antifungal gut mycobiome Candida intestinal colonization") returned only Candida-infection-treatment and antifungal-resistance papers, not compositional or diversity studies. A mechanistic candidate was weighed explicitly: the RECORLEV label cites substantial fecal excretion (57% of a racemic ketoconazole dose, per label PK data) alongside ketoconazole's known broad antifungal spectrum against gut-resident fungi such as Candida, which could in principle mean meaningful luminal azole exposure. This reasoning could not be anchored to any actual compositional or functional gut-microbiome measurement, drug-specific or class-level, and no data comparing levoketoconazole's own residual antifungal (ergosterol-pathway) potency to that of racemic ketoconazole was located, so even the class-level extrapolation carries unresolved uncertainty. This revision broadened the search a further step beyond the fungal/mycobiome angle to ask whether systemic antifungal drugs alter the gut bacterial microbiome generally, not just its fungal component; a PubMed search-listing check ("antifungal prophylaxis gut bacterial microbiome diversity") returned no studies on systemic antifungal drugs and bacterial microbiome composition or diversity, only unrelated antibiotic, vaccine, probiotic, and insect-model studies. Per instruction, the mycobiome mechanism remains disclosed as considered-but-unsubstantiated rather than used to justify a yellow grade. No consumer claim was found either.

Search channels tried

Crossref works API (multiple phrasings across the original review and this revision: "ketoconazole gut microbiome", "ketoconazole gut microbiota", "azole antifungal zinc status deficiency" as an adjacent trace-mineral/mycobiome check, "oral azole antifungal gut mycobiome Candida intestinal colonization"), PubMed search-listing pages ("ketoconazole intestinal fungi mycobiome" and "ketoconazole gut microbiota" returned zero results in the original review; "antifungal prophylaxis gut bacterial microbiome diversity" returned no relevant results in this revision). Europe PMC's REST API and the Semantic Scholar API were retried multiple times, spaced out, in this revision and again returned persistent HTTP 403 gateway-level connection rejections on every attempt; they remain unusable. WebSearch was unavailable this session as well. This is now a second consecutive genuine multi-channel attempt with the same result; a future revision should re-try Europe PMC and Semantic Scholar specifically once gateway access to those hosts is restored, and should check whether levoketoconazole retains meaningful antifungal potency relative to racemic ketoconazole before revisiting this category.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

ATP production, same source, direct measurement of reduced output

Yellow — Low

See study details

The same in vitro study directly measured reduced ATP production in ketoconazole-exposed human hepatocytes, the only direct ATP measurement located for this drug or its class in the literature searched.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: None specific; this is the positive finding itself, and no contradicting null ATP measurement for this drug class was located.
  • At-risk subgroups: Same as the Mitochondrial burden entry.
  • Counter-evidence on record: None found for levoketoconazole; not tested with the pure enantiomer.

Regulatory status

Not addressed in the label.

Population evidence

Haegler et al 2017 (PMID 28329820): "reduced ATP production" reported alongside the complex I and superoxide findings in HepG2 cells exposed to ketoconazole. Tier C for levoketoconazole.

Mechanism

Named: direct consequence of complex I impairment reducing oxidative phosphorylation capacity.

Counter-evidence held on record

In vitro, cytotoxic-concentration, class-level evidence only, sharing its single source with the Mitochondrial burden and Oxidative stress entries above (see Overlap map). Not a basis for any energy-support supplement recommendation.

Oxygen delivery/utilization, mechanistic via labeled testosterone suppression, no direct hemoglobin data

Yellow — Low

See study details

RECORLEV's own label quantifies a real, if modest, rate of hypogonadism and testosterone lowering, and testosterone is an established stimulant of erythropoiesis; suppressing it is a recognized cause of reduced hemoglobin and hematocrit in other clinical settings, though no hemoglobin, hematocrit, or anemia finding was reported for levoketoconazole or ketoconazole themselves in any source located.

Full detail, limits and 2 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: Neither pivotal trial's adverse-reaction tables (Tables 2 and 3, which separately and precisely quantify hypogonadism, hypokalemia, hypertension, and edema) list anemia, low hemoglobin, or any hematologic finding, despite hemoglobin being a routine, easily measured safety lab that would likely have been flagged in the same tables if a meaningful signal existed at the modest degree of testosterone suppression RECORLEV produces.
  • At-risk subgroups: Not established for levoketoconazole specifically. By analogy to the ADT literature, any effect would be expected to be concentrated in the minority of patients who develop clinically apparent hypogonadism (2 to 4% per the label) rather than across the treated population generally.
  • Counter-evidence on record: The absence of any hemoglobin or anemia signal in either pivotal trial's precisely quantified adverse-reaction tables, despite RECORLEV's own testosterone-suppression data being reported in the same tables, is itself a meaningful negative finding and is recorded as such, alongside the much greater degree of testosterone suppression in the ADT literature relied on for the mechanism.

Regulatory status

Label Section 5.5 warns of decreased testosterone; Section 6.1 quantifies hypogonadism at 2% in Study 1 (Table 2) and 4% in Study 2 (Table 3), alongside decreased libido (5%) and gynecomastia (3%) in Study 2. The label was searched specifically for "hemoglobin," "hematocrit," "anemia," "red blood cell," and "erythrocyte"; none of those terms appear anywhere in the current label text.

Population evidence

No study measuring hemoglobin, hematocrit, or red-cell mass in levoketoconazole- or ketoconazole-treated patients was located after a renewed multi-channel search in this revision. The supporting mechanism is a class-unrelated but directly on-point study: Gagliano-Jucá, Pencina, Ganz, Travison, Kantoff, Nguyen, Taplin, Kibel, Li, Huang, Edwards, Nemeth, Basaria 2018 (American Journal of Physiology-Endocrinology and Metabolism 315(6):E1185-E1193, DOI 10.1152/ajpendo.00272.2018), a prospective cohort of 70 men (31 on androgen-deprivation therapy, 39 controls) over 6 months, found ADT was associated with a significant reduction in erythrocyte count, hematocrit, and hemoglobin, attributed to reduced proliferation of marrow erythroid progenitors, with serum hepcidin rising while iron itself stayed stable. Tier C for levoketoconazole: androgen-deprivation drugs (GnRH agonists/antagonists), not levoketoconazole or ketoconazole, were the tested agents. Warren and Grossmann 2022 (Best Practice & Research Clinical Endocrinology & Metabolism 36(5):101653, DOI 10.1016/j.beem.2022.101653), a review titled "Haematological actions of androgens," was also located and its topic/MeSH indexing (erythropoiesis, testosterone, erythropoietin, androgen deprivation therapy, anemia) confirms the same general mechanism; its full abstract text could not be retrieved through any channel tried, so it is cited here at the level confirmed by its title and indexing only.

Mechanism

Named, two steps removed from a direct drug-hemoglobin measurement: androgens, including testosterone, stimulate erythropoiesis, in part by suppressing hepcidin and increasing erythropoietin sensitivity; suppressing testosterone reduces marrow erythroid progenitor proliferation and lowers hemoglobin, hematocrit, and red-cell count, as directly measured in the Gagliano-Jucá 2018 ADT cohort. RECORLEV's own label confirms it lowers testosterone and causes hypogonadism in a quantified minority of patients (2 to 4%), a smaller and almost certainly less complete degree of androgen suppression than the depot GnRH-agonist ADT regimens studied by Gagliano-Jucá, which produce near-total testosterone suppression.

Counter-evidence held on record

This is a mechanistic hypothesis built by connecting RECORLEV's own quantified but modest testosterone-suppression data to an established literature on a different drug class (androgen deprivation) and anemia; it is not a demonstrated hemoglobin or hematocrit deficit in RECORLEV-treated patients, and the negative finding in both pivotal trials' own safety tables argues against a large effect at labeled doses. No iron, B12, or other anemia-directed supplement recommendation is implied by this entry; any hematologic concern should be evaluated by a clinician against RECORLEV's own boxed hepatotoxicity and QT-prolongation monitoring requirements.

All references used above
  1. RECORLEV (levoketoconazole) prescribing information — DailyMed, Xeris Pharmaceuticals, SetID d4c5fead-bc4a-fb02-e053-2a95a90ae4fc. Sections: mechanism of action, pharmacokinetics, boxed warnings, warnings and precautions, dosage/monitoring, drug interactions, adverse reactions (Tables 1-5), use in specific populations.
  2. WHO ATC/DDD Index, code H02CA04 — Confirms levoketoconazole classification under H02CA, "Corticosteroid antagonists: enzyme inhibitors."
  3. Fleseriu M, Pivonello R, Elenkova A, Salvatori R, Auchus RJ, Feelders RA, Geer EB, Greenman Y, Witek P, Cohen F, Biller BMK. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. — The Lancet Diabetes & Endocrinology, 2019. n=84 safety population, single-arm. This is Study 1 in the FDA label.
  4. Pivonello R, Zacharieva S, Elenkova A, Tóth M, Shimon I, Stigliano A, Badiu C, Brue T, Georgescu C, Tsagarakis S, Cohen F, Fleseriu M. Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). — Pituitary, 2022. n=94 active-drug safety population, randomized withdrawal design. This is Study 2 in the FDA label. PMID 36085339.
  5. Patra S, Dutta D, Nagendra L, Raizada N. Efficacy and Safety of Levoketoconazole in Managing Cushing's Syndrome: A Systematic Review. — Indian Journal of Endocrinology and Metabolism, 2024. Drug-specific systematic review of the SONICS/LOGICS clinical program. PMID 39371660.
  6. Creemers SG, Feelders RA, de Jong FH, et al. Levoketoconazole, the 2S,4R Enantiomer of Ketoconazole, a New Steroidogenesis Inhibitor for Cushing's Syndrome Treatment. — 2021. In vitro adrenocortical (HAC15) and corticotroph (AtT20) cell models; levoketoconazole cortisol IC50 0.300 µM vs racemic ketoconazole 0.611 µM (P<0.0001). PMID 33399817.
  7. Pivonello R, Elenkova A, Fleseriu M, Feelders RA, Witek P, et al. Levoketoconazole in the Treatment of Patients With Cushing's Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study. — Frontiers in Endocrinology, 2021. Diabetes-mellitus subgroup analysis (n=28) of the SONICS trial. PMID 33897615.Full abstract narrative not retrievable through OpenAlex's inverted-index metadata; only partial adverse-event figures (nausea, vomiting, UTI) were confirmed.
  8. Engelhardt D, Mann K, Hörmann R, Braun S, Weber MM. The influence of ketoconazole on serum levels of cortisol, 11-deoxycortisol, corticosterone and 11-deoxycorticosterone in normals and in patients with Cushing's syndrome. — Acta Endocrinologica, 1984. Directly measured DOC accumulation with ketoconazole (racemic) in healthy subjects and Cushing's patients; cited here as Tier C mechanistic confirmation for levoketoconazole.Class-level source: ketoconazole (racemic), not levoketoconazole, was the tested compound.
  9. Constantopoulos G, et al. The mineralocorticoid activity of 18-hydroxy-11-deoxycorticosterone, 11-deoxycorticosterone, and aldosterone in the adrenalectomized dog. — Canadian Journal of Physiology and Pharmacology, 1979. Background reference confirming DOC's mineralocorticoid/potassium-wasting activity; no levoketoconazole or ketoconazole involvement, cited as physiological background only.Background physiology reference; drug not in cohort.
  10. Haegler P, Joerin L, Krähenbühl S, Bouitbir J. Hepatocellular Toxicity of Imidazole and Triazole Antimycotic Agents. — Toxicological Sciences, 2017, 157(1):183-195. Isolated mouse liver mitochondria and human HepG2/HepaRG cells; ketoconazole impaired complex I activity and membrane potential, reduced ATP production, and increased superoxide, at 20-100 µM. PMID 28329820.Class-level source: ketoconazole (racemic), not levoketoconazole, was the tested compound.
  11. Gupta RP, Hollis BW, Patel SB, Patrick KS, Bell NH. CYP3A4 is a human microsomal vitamin D 25-hydroxylase. — Journal of Bone and Mineral Research, 2004. Identified CYP3A4 as the recombinant human enzyme with highest vitamin D 25-hydroxylase activity among 16 screened; activity inhibited by "recognized CYP3A4 inhibitors." PMID 15005856.Mechanistic/enzyme-class source; retrievable abstract did not confirm ketoconazole by name as the specific inhibitor tested in this study.
  12. Nguyen M, Boutignon H, Mallet E, Linglart A, et al. Infantile Hypercalcemia and Hypercalciuria: New Insights into a Vitamin D-Dependent Mechanism and Response to Ketoconazole Treatment. — Journal of Pediatrics, 2010. Case report; ketoconazole used therapeutically to suppress excess active vitamin D via steroidogenic-enzyme-family inhibition. PMID 20394945.Full abstract text not retrievable (paywalled; no open-access copy found via Unpaywall). Cited at the level confirmed by title and MeSH indexing only. Class-level: ketoconazole, not levoketoconazole.
  13. Peehl DM, Seto E, Feldman D. Rationale for combination ketoconazole/vitamin D treatment of prostate cancer. — 2001. Describes ketoconazole potentiating vitamin D analogue activity via CYP24A1 (catabolic enzyme) inhibition, a direction opposite to the Nguyen 2010 finding. PMID 11502466.Full abstract narrative not retrievable through available metadata; mechanism summarized from title and indexed MeSH terms. Class-level: ketoconazole, not levoketoconazole.
  14. Drug Interaction Study of Levoketoconazole and Metformin. — Clinical trial NCT03880825, 2019, cited directly in the RECORLEV label's drug-interaction table (Table 6/8) as the source of the metformin AUC +220% figure. Levoketoconazole and metformin co-administered; drug directly in cohort.
  15. Thieroff-Ekerdt R, Mould D. Differentiated pharmacokinetics of levoketoconazole (COR-003), the single 2S,4R-enantiomer of ketoconazole, a new investigational drug for the treatment of Cushing's syndrome. — Endocrine Abstracts, 2016. Supportive PK context for the enantiomer-specific dossier.
  16. Ketoconazole. [Case report: apparent mineralocorticoid excess.] — Reactions Weekly, 2020, Vol 1794(1):136. Case documentation of ketoconazole-associated apparent mineralocorticoid excess, corroborating the Potassium/Sodium mechanism at the class level.Class-level source; brief case-report summary, ketoconazole not levoketoconazole.
  17. Deering TB, Dickson ER, Fleming CR, Geall MG, McCall JT, Baggenstoss AH. Effect of D-penicillamine on copper retention in patients with primary biliary cirrhosis. — Gastroenterology, 1977, 72(6):1208-1212. Directly measured hepatic copper retention in primary biliary cirrhosis and its mobilization by D-penicillamine; cited in this revision as Tier C mechanistic support for the Copper entry's cholestasis-retention hypothesis.Class-level source: primary biliary cirrhosis, a chronic structural cholestatic disease, not levoketoconazole or ketoconazole hepatotoxicity, and drug not in cohort.
  18. Gagliano-Jucá T, Pencina KM, Ganz T, Travison TG, Kantoff PW, Nguyen PL, Taplin ME, Kibel AS, Li Z, Huang G, Edwards RR, Nemeth E, Basaria S. Mechanisms responsible for reduced erythropoiesis during androgen deprivation therapy in men with prostate cancer. — American Journal of Physiology-Endocrinology and Metabolism, 2018, 315(6):E1185-E1193. Prospective cohort, 31 men on androgen-deprivation therapy vs 39 controls, 6 months; ADT significantly reduced erythrocyte count, hematocrit, and hemoglobin via reduced marrow erythroid progenitor proliferation, with rising hepcidin and stable iron. Cited in this revision as Tier C mechanistic support for the Oxygen delivery/utilization entry.Class-level source: androgen-deprivation therapy (GnRH agonists/antagonists), not levoketoconazole or ketoconazole, was the tested intervention.
  19. Warren AM, Grossmann M. Haematological actions of androgens. — Best Practice & Research Clinical Endocrinology & Metabolism, 2022, 36(5):101653. Review of androgens' effects on erythropoiesis and anemia in androgen-deprived states. Cited in this revision alongside Gagliano-Jucá 2018 for the Oxygen delivery/utilization entry.Full abstract text not retrievable through any channel tried (Crossref and OpenAlex both returned no abstract field); cited at the level confirmed by title, journal indexing, and topic/MeSH metadata only. Class-level source; drug not in cohort.