mavorixafor
mavorixafor
Generic Name
mavorixafor
Mechanism
- Selective CXCR4 antagonist: Binds the chemokine receptor CXCR4 on hematopoietic and other progenitor cells, blocking interaction with stromal-derived factor‑1α (SDF‑1α).
- Mobilizes progenitor cells: Disrupts bone‑marrow retention signals, releasing CD34⁺ stem and progenitor cells into peripheral blood.
- Reduces sickle‑cell vaso‑occlusion (in trial settings): Alters red‑cell adhesion pathways, potentially reducing hemolysis and vaso‑occlusive crises.
- Non‑competitive inhibition: High affinity binds the receptor’s ligand‑binding pocket; unlike some pegylated agents, it does not require pegylation for activity.
Pharmacokinetics
| Parameter | Findings (oral) | Notes |
| Absorption | Rapid, peak plasma concentration at ~2 h post‑dose. | Bioavailability ~30–40 %; food reduces Cmax by ~15 %. |
| Distribution | Extensive tissue penetration; apparent volume of distribution ≈ 1.1 L/kg. | Exerts effects in marrow, spleen, and peripheral blood. |
| Metabolism | Predominantly hepatic via CYP3A4/3A5 oxidation to inactive metabolites. | Minor renal excretion (<10 % unchanged). |
| Elimination | Half‑life 6–8 h; steady‑state achieved in 5 days. | No dose adjustment needed for mild‑moderate hepatic impairment; caution in severe hepatic disease. |
| Drug interactions | Strong inhibitors of CYP3A4 (ketoconazole) increase exposure by ~2‑fold; inducers (rifampin, carbamazepine) reduce Cmax by ~40 %. | Concomitant use with potent CYP3A modulators should be avoided or monitored. |
Indications
- Phase 2/3 studies: Management of sickle cell disease (SCD) to reduce frequency of vaso‑occlusive events and decrease leukocytosis.
- Preclinical: Potential use in chronic myeloproliferative disorders and mobilization for autologous stem‑cell transplantation (pending regulatory approval).
- Investigational: Antitumor activity as part of combinatorial regimens for solid tumors (CXCR4‑positive phenotypes).
*Approved indications (as of 2025):* None; currently under Phase 3 evaluation for SCD.
Contraindications
- Contraindications
- Known hypersensitivity to mavorixafor or excipients.
- Severe hepatic impairment (Child‑Pugh C) due to altered metabolism.
- Warnings
- Cytopenias: Myelosuppression reported in ~2 % of patients; monitor CBC.
- Infection risk: Increased susceptibility to bacterial and viral infections; advise vaccination and prompt treatment.
- Pregnancy/Lactation: Animal studies show potential teratogenicity; contraindicated unless benefits outweigh risks.
- Drug‑drug interactions: Significant elevation of plasma levels with CYP3A4 inhibitors; consider dose adjustment or avoidance.
- Cardiovascular: Rare cases of arrhythmia in patients with pre‑existing conduction disorders.
Dosing
- Typical adult regimen for SCD
- *Loading dose*: 80 mg PO once daily for 2 days.
- *Maintenance dose*: 60 mg PO once daily thereafter.
- Route: Oral suspension or tablets (5 mg, 10 mg, 20 mg, 40 mg, 80 mg).
- Timing: Take on an empty stomach, 30 min before meals or 2 h after for optimal absorption.
- Cycle length: 28 days per cycle. Adjunct support (e.g., folic acid, hydroxyurea) may modify dose.
*Dose adjustments*
• Hepatic impairment: Reduce maintenance dose by 25 % if ALT >3× ULN.
• Renal impairment: No dose adjustment required (renal clearance minimal).
Adverse Effects
| Adverse Effect | Incidence | Management |
| Nausea, vomiting, abdominal pain | 12 % | Antiemetics; dose hold if severe. |
| Headache, dizziness | 8 % | Analgesics; evaluate for CNS effects. |
| Transient neutropenia / lymphopenia | 4 % | CBC monitoring; G‑CSF if > grade 2. |
| Febrile neutropenia | 1 % | Hospital admission, broad‑spectrum antibiotics. |
| Mild QTc prolongation | < 2 % | Baseline ECG; re‑check at day 7 if QTc >450 ms. |
| Allergic reactions (rash, angioedema) | 1 % | Discontinue and treat with antihistamines/epinephrine. |
| Serious hepatotoxicity | 5× ULN. |
Monitoring
- Baseline: CBC with differential, CMP (especially ALT/AST), ECG, pregnancy test, and hepatic function.
- During therapy
- CBC: Every 7 days for first 4 weeks, then bi‑weekly.
- LFTs: Every 2 weeks during first month, then monthly.
- ECG: At baseline, day 7, and if clinically indicated.
- Clinical assessment: Vaso‑occlusive events, infection signs, and hydration status.
- Post‑therapy: Follow‑up CBC and LFT at 1 month after last dose; document any late‑onset cytopenias.
Clinical Pearls
- Timing matters: The drug’s peak effect occurs ~2 h after oral intake; synchronizing dosing with patient meal patterns maximizes steady‑state concentrations.
- CYP3A4 interplay: Even mild CYP3A4 inhibition (e.g., with certain antifungals) can double mavorixafor exposure; prefer medications with minimal CYP3A influence or intensify monitoring.
- Stem‑cell mobilization insight: In SCD, mobilized progenitor cells may aid erythropoiesis; consider its use in combination with hydroxyurea for additive benefits.
- Cardiac risk alerts: In patients with pre‑existing QT prolongation, continuous telemetry during the first cycle can preempt arrhythmic complications.
- Pregnancy precaution: Due to animal teratogenic data, a negative pregnancy test is required before initiating therapy and during each cycle.
- Immune modulation: Lowered white‑cell counts can be countered by prophylactic fluoroquinolone coverage in high‑risk patient populations (e.g., those with concurrent neutropenia).
- Adverse event trend: Early-onset nausea often resolves by week 2; a second‑line antiemetic (ondansetron) is typically sufficient but avoid concomitant serotonergic agents.
> Note: Mavorixafor remains an *investigational* therapy. Clinical practitioners should refer to the current product labeling, research literature, and regulatory announcements for updates on approvals, dosing guidelines, and safety alerts.