Mavorixafor

Introduction Overview

Generic Name

mavorixafor

Brand Name

Xolremdi

Dosage Form

oral capsule (100 mg)

Drug Class

Other immunostimulants; CXCR4 chemokine receptor antagonists

Pharmacokinetics

Absorption:
Mavorixafor (Xolremdi) is administered orally as a capsule and exhibits good bioavailability when taken on an empty stomach. Clinical administration recommends dosing once daily in the morning after an overnight fast with at least 30 minutes before eating to ensure optimal absorption. The pharmacokinetic profile shows that food intake can reduce the rate and extent of absorption; thus, fasting is essential for consistent plasma levels. Peak plasma concentrations are typically reached within a few hours post-administration, supporting once-daily dosing.

Distribution:
Following absorption, mavorixafor distributes into body tissues with a moderate volume of distribution indicating both vascular and extravascular tissue penetration. It selectively targets the CXC chemokine receptor 4 (CXCR4) expressed on immune cells and other tissues. Plasma protein binding and tissue affinity data suggest that the drug achieves sufficient concentrations in the bone marrow microenvironment, crucial for its therapeutic role in WHIM syndrome. The distribution profile supports its ability to reach sites of immune cell retention in the bone marrow.

Metabolism:
Mavorixafor is metabolized primarily via hepatic cytochrome P450 pathways, notably involving CYP3A4 and CYP2D6 isoenzymes. This metabolic pathway explains drug interactions with CYP3A4 inhibitors (e.g., itraconazole, grapefruit) and CYP2D6 substrates or inhibitors (e.g., fluoxetine, amitriptyline). The metabolic clearance rate can be influenced by concomitant medications and organ function, necessitating consideration in patients with liver impairment. No active metabolites with significant pharmacological activity have been identified, and the parent compound is responsible for the therapeutic effect.

Elimination:
The elimination of mavorixafor occurs primarily via hepatic metabolism followed by biliary and renal excretion of metabolites and unchanged drug. The half-life supports once-daily dosing and is sufficiently long to maintain plasma concentrations over 24 hours. Renal excretion plays a key role in clearance, and accumulation can occur in patients with severe renal impairment; therefore, Xolremdi is contraindicated in patients with end-stage renal disease or moderate to severe kidney disease. Hepatic impairment also affects clearance, and the drug is not recommended in moderate to severe liver disease. Monitoring of organ function is advised to prevent toxicity.

Dosage Forms

Available Dosage Forms:
Xolremdi is available exclusively as an oral hard gelatin capsule containing 100 mg of the active ingredient mavorixafor. The capsule includes inactive ingredients such as colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate dihydrate, microcrystalline cellulose, sodium lauryl sulfate, sodium stearyl fumarate, and capsule shell components including FD&C Blue No. 2 and other coloring agents for identification.

Dosages for Adults and Adolescents:
Dosing is weight-based for patients 12 years and older with WHIM syndrome. For individuals weighing more than 50 kg, the recommended dose is 400 mg orally once daily, corresponding to 4 capsules. For those weighing 50 kg or less, the dose is 300 mg orally once daily, equivalent to 3 capsules. The capsules must be taken on an empty stomach in the morning following an overnight fast and at least 30 minutes before breakfast to ensure optimal absorption and therapeutic efficacy.

Specific Patient Populations:
Xolremdi is not recommended in patients with moderate to severe liver impairment or severe to end-stage renal disease due to altered pharmacokinetics leading to increased exposure and potential toxicity. Special consideration is advised for females of childbearing potential who must use effective contraception during treatment and for 3 weeks after the last dose to prevent fetal harm. Pediatric dosing below 12 years has not been established. Elderly patients should be monitored carefully for adverse effects but no specific dose adjustment has been clearly defined. Patients with cardiac arrhythmias or predisposition to QT prolongation require ECG monitoring and correction of electrolyte abnormalities prior to therapy. Concomitant use with CYP3A4 inhibitors, CYP2D6 substrates, or QT prolonging medications necessitates careful evaluation and possible dose modification.

Mechanism Of Action

Mavorixafor (Xolremdi) functions as a selective antagonist of the CXC chemokine receptor 4 (CXCR4), a G-protein coupled receptor critical in immune cell trafficking and retention within the bone marrow. In WHIM syndrome, mutations in the CXCR4 receptor enhance its response to its ligand stromal derived factor-1α (SDF-1α or CXCL12), resulting in pathologically increased retention of mature neutrophils and other immune cells in the bone marrow, leading to peripheral cytopenias.

By competitively inhibiting the binding of CXCL12 to CXCR4, mavorixafor disrupts this pathological retention signal, thereby promoting the mobilization of mature neutrophils, lymphocytes, and other immune cells from the bone marrow into the peripheral bloodstream. This restoration of circulating immune cell levels helps reduce infection susceptibility and ameliorates immune dysregulation characteristic of WHIM syndrome.

At the molecular level, mavorixafor binding alters CXCR4 conformation, inhibiting downstream Gi protein signaling pathways that normally mediate chemotaxis, adhesion, and homing of hematopoietic and immune cells. This interruption reduces CXCR4-mediated intracellular calcium flux, chemotactic migration, and cellular retention in the bone marrow microenvironment.

Clinically, this mechanism results in increased neutrophil counts and improved immune functionality in WHIM patients, as demonstrated in clinical trials with significant increases in circulating mature neutrophils and lymphocytes post-treatment. Mavorixafor's potency extends to both wild-type and the mutated CXCR4 receptors associated with WHIM, highlighting its targeted and specific therapeutic action in this rare immunodeficiency. Compared to other immunostimulants or mobilizers, mavorixafor provides a unique receptor antagonist approach, directly correcting the underlying receptor hyperactivity rather than nonspecifically stimulating bone marrow activity.

Pharmacological Actions

Selective antagonism of the CXCR4 receptor to disrupt pathological retention of immune cells in bone marrow.
Mobilization of mature neutrophils, lymphocytes, and other white blood cells into peripheral circulation.
Restoration of normal immune cell counts in patients with WHIM syndrome.
Inhibition of CXCL12-induced intracellular signaling pathways, including calcium flux and chemotaxis.
Reduction of lymphocyte and neutrophil sequestration within bone marrow microenvironment.
Correction of immune dysfunction caused by gain-of-function CXCR4 mutations.
Enhancement of host defense through improved leukocyte availability in bloodstream.
Targeted modulation of chemokine receptor activity without broad bone marrow stimulation.
Oral bioavailability facilitating once-daily administration.
Minimal off-target effects due to receptor specificity.
Demonstrated efficacy in normal and mutant CXCR4 receptor variants relevant to WHIM.
Potential to reduce infection risks by normalizing peripheral immune cell counts.
Interference with processes leading to wart formation and immunosuppression in WHIM patients.
Pharmacodynamic effect sustained over 24 hours supporting convenient dosing.

Therapeutic Or Clinical Uses

Treatment of WHIM syndrome in adults and children 12 years and older.
Increase in circulating mature neutrophils and lymphocytes in WHIM patients.
Reduction of infection frequency and severity related to immune cell deficits.
Management of immunodeficiency caused by CXCR4 gain-of-function mutations.
Improvement of quality of life and immune function in rare genetic immunodeficiency.
Potential reduction in HPV-associated wart burden associated with WHIM.
Adjunct to routine monitoring and prophylactic measures in WHIM syndrome management.
Facilitation of normalization of antibody production in patients with hypogammaglobulinemia.
Treatment option aimed at underlying pathophysiology rather than symptoms alone.
Use as an oral, once-daily therapy improving patient adherence.
Off-label exploration in other conditions with CXCR4 mediated immune retention may be considered with further research.
Reduction of complications related to low peripheral immune cell counts.
Therapeutic alternative to hematopoietic growth factors which have broader effects.
FDA approved since April 26, 2024, as a novel agent for WHIM syndrome.

Side Or Adverse Effects

Thrombocytopenia (low platelet counts) potentially increasing bleeding risk.
Pityriasis rash presenting as oval, scaly, pinkish lesions on skin.
Upper respiratory symptoms including nasal congestion, sneezing, and stuffiness.
Epistaxis (nosebleeds) reported during treatment courses.
Gastrointestinal disturbances such as vomiting.
Dizziness possibly related to pharmacodynamic effects.
QTc interval prolongation observed in clinical trials increasing arrhythmia risk.
Potential for hypersensitivity reactions including allergic skin manifestations.
Risk of fetal harm necessitating contraceptive measures.
Possible exacerbation of preexisting skin conditions.
Adverse reactions may be exacerbated by concomitant medications affecting QTc or CYP pathways.
Rare but serious effects on cardiac conduction requiring ECG monitoring.
Injection site reactions are not applicable as the drug is oral, minimizing local adverse effects.
Uncommon laboratory abnormalities including changes in liver or renal function may occur.
Other adverse events not fully enumerated; patients should report unexpected symptoms promptly.

Precautions

Use with caution in patients with preexisting cardiac conduction abnormalities or arrhythmias.
Regular ECG monitoring is recommended to assess QTc interval before and during treatment.
Avoid use in patients with moderate to severe liver impairment due to altered metabolism.
Contraindicated in severe kidney disease and end-stage renal disease due to clearance concerns.
Avoid concomitant use with drugs highly dependent on CYP2D6 pathways, such as fluoxetine and amitriptyline.
Prevent hypokalemia or other electrolyte disturbances that can increase QT prolongation risk.
Females of reproductive potential must use effective contraception during treatment and for 3 weeks post-therapy.
Pregnancy is contraindicated due to demonstrated fetal toxicity and abnormal placental development.
Do not breastfeed during treatment and for 3 weeks after the last dose to prevent infant exposure.
Advise patients to report any signs of bleeding, rash, or cardiovascular symptoms promptly.
Avoid grapefruit products and goldenseal which may increase mavorixafor plasma levels.
Be cautious with combined use of CYP3A4 inhibitors which can increase drug exposure.
Monitor platelet counts and other hematological parameters regularly.
Screen for drug interactions comprehensively before initiating therapy.
Inform patients about the importance of adherence to fasting administration guidelines.

Warnings

Risk of fetal harm and abnormal placental development; strict contraception required.
QTc interval prolongation with potential for life-threatening arrhythmias.
Avoid use in moderate to severe hepatic or severe renal impairment due to toxicity risk.
Potential interactions with CYP2D6 and CYP3A4 substrates can increase side effect profile.
Concomitant use with QTc prolonging drugs can exacerbate cardiac risks.
Increased bleeding risk due to thrombocytopenia; monitor platelet counts carefully.
Hypersensitivity or severe rash may require treatment discontinuation.
Avoid abrupt discontinuation that may affect immune cell dynamics, monitor clinical status.
Patients should be advised about signs of cardiac events like palpitations or syncope.
Not studied in pediatric patients younger than 12 years; safety not established.
Efficacy and safety in pregnancy and lactation have not been established.
Clinical monitoring necessary for possible drug-drug interaction related adverse events.
Storage considerations require refrigeration to maintain drug stability.
Medication errors may occur if dosing based on weight is not strictly followed.
Advise patients to avoid herbal supplements that may interfere with drug metabolism.

Contraindication

Severe kidney disease or end-stage renal disease.
Moderate to severe hepatic impairment.
Pregnancy due to teratogenicity and fetal harm risk.
Known hypersensitivity to mavorixafor or any capsule excipients.
Concomitant use with strong CYP2D6 inhibitors or substrates with narrow therapeutic indices.
Preexisting dangerously prolonged QTc interval uncorrected prior to treatment.
Use in pediatric patients under 12 years of age is contraindicated due to lack of safety data.
Patients with active severe infections requiring systemic treatment without immune stabilization.
Breastfeeding during treatment and up to 3 weeks after last dose.
Concomitant use with potent CYP3A4 inhibitors without dose adjustment.
Use with other investigational immunostimulants without evidence of safety.
Concurrent use with drugs causing severe hypokalemia or electrolyte imbalance without correction.
Any condition where immune stimulation could exacerbate disease, such as active malignancy outside WHIM-associated cancers without oncologist approval.
Contraindicated if unable to comply with fasting dosing requirements.
Hypersensitivity reactions to gelatin or capsule components (e.g., FD&C Blue #2) in susceptible individuals.

Drug Interactions

Strong CYP3A4 inhibitors (itraconazole, grapefruit) can increase mavorixafor plasma concentrations and risk of toxicity.
CYP2D6 substrates or inhibitors (fluoxetine, amitriptyline) contraindicated due to competitive metabolism leading to increased levels.
Other QTc prolonging agents (haloperidol, amiodarone, sotalol, ondansetron) increase risk of cardiac arrhythmias when used concurrently.
P-glycoprotein substrates (digoxin, metformin) may have altered absorption or clearance with mavorixafor coadministration.
St. John's Wort may reduce efficacy of Xolremdi by inducing CYP3A4 enzymes enhancing clearance.
Medications causing hypokalemia (diuretics such as furosemide) may augment QT prolongation risk.
Goldenseal consumption may increase drug levels and enhance adverse reactions.
Concomitant use with other immunostimulants or chemokine receptor modulators has not been studied and should be avoided.
Concomitant CYP3A4 inducers may reduce plasma levels and therapeutic effect.
Herbal supplements affecting cytochrome P450 enzymes could unpredictably alter mavorixafor pharmacokinetics.
Drugs affecting gastrointestinal motility may influence absorption rate and peak concentrations.
Concurrent use of strong CYP3A4 substrates may increase competition for metabolism and alter drug levels.
Multiple concomitant drugs requiring dose adjustment and clinical monitoring to prevent toxicity.
Drug interactions could lead to increased risk of thrombocytopenia or immune suppression.
Close monitoring required when initiating or discontinuing interacting drugs.

Preparations Of The Drug

Mavorixafor 100 mg oral hard gelatin capsules (Xolremdi).
Packaging includes spoilage-protective container to maintain moisture protection.
Refrigerated storage required at 2°C to 8°C (36°F to 46°F).
Capsule shell contains FD&C Blue No. 2, gelatin, and titanium dioxide for identification.
Inert excipients include colloidal silicon dioxide, croscarmellose sodium, microcrystalline cellulose, sodium lauryl sulfate, sodium stearyl fumarate, dibasic calcium phosphate dihydrate.
Black ink printing includes ammonium hydroxide, black iron oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze in ethanol.
Supplied by X4 Pharmaceuticals, Inc., based in Boston, focusing on rare disease therapeutics.
No generic equivalents currently available.
Each capsule contains a uniform dose ensuring consistent bioavailability.
Batch-specific quality control ensures purity and potency according to FDA standards.
Storage guidance emphasizes keeping capsules in original container with tight closure to avoid moisture degradation.
Capsules must not be crushed or opened to maintain drug stability and absorption profile.
Patient counseling on proper storage and handling to maintain efficacy.
Avoid exposure to excessive heat or freezing temperatures.