Chemokine receptor antagonist

Overview
Chemokine receptor antagonists are a targeted class of drugs that block specific chemokine receptors, thereby inhibiting the binding and activity of their natural chemokine ligands. This prevents leukocyte trafficking and other downstream immune processes mediated by chemokines. They have been explored for a variety of clinical indications, particularly in HIV infection, autoimmune diseases, and inflammatory disorders.

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Mechanism of Action

• Chemokines are small cytokines that bind to G protein–coupled receptors (GPCRs) on leukocytes and other cells.

• By blocking these receptors, chemokine receptor antagonists inhibit chemokine–receptor interaction and the subsequent intracellular signaling cascade.

• This reduces leukocyte chemotaxis, inflammation, or, in the case of HIV, viral entry into host cells (some HIV strains require chemokine co-receptors to infect cells).

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Main Types and Examples

1. CCR5 Antagonists

   • Example: Maraviroc – the only widely approved chemokine receptor antagonist for clinical use.

   • Mechanism: Binds to the CCR5 receptor on CD4⁺ T cells, blocking the interaction with HIV-1 gp120. This prevents entry of CCR5-tropic HIV strains into cells.

   • Therapeutic Use: In combination antiretroviral therapy for CCR5-tropic HIV-1 infection (requires tropism testing before use).

2. CXCR4 Antagonists

   • Example: Plerixafor – primarily used for hematopoietic stem cell mobilization, not marketed as an anti-HIV drug.

   • Mechanism: Blocks CXCR4–SDF-1 (CXCL12) interaction, mobilizing stem cells into peripheral blood for collection and transplantation.

3. Investigational / Autoimmune-Targeted Agents

   • Multiple CCR1, CCR2, CCR9, and CXCR3 antagonists have been studied for conditions such as multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and asthma, but most remain experimental.

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Therapeutic Uses

• Maraviroc:

  • HIV-1 infection (CCR5-tropic only) in treatment-experienced or selected treatment-naïve patients as part of combination ART.

• Plerixafor:

  • Mobilization of hematopoietic stem cells in patients with non-Hodgkin lymphoma or multiple myeloma in combination with granulocyte-colony stimulating factor (G-CSF).

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Dosing (Selected Agents)

• Maraviroc: 150 mg, 300 mg, or 600 mg orally twice daily, adjusted based on concomitant CYP3A4 inhibitor/inducer use and renal function.

• Plerixafor: 0.24 mg/kg subcutaneously once daily, usually for 4 days, in conjunction with G-CSF.

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Contraindications

• Known hypersensitivity to the agent or formulation components.

• For maraviroc: severe renal impairment with concurrent potent CYP3A4 inhibitors, unless benefits outweigh risks.

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Precautions

• Maraviroc: Monitor for hepatotoxicity, postural hypotension, and cardiovascular events.

• Plerixafor: Risk of splenic enlargement/rupture; caution in patients with leukemia (mobilization of malignant cells possible).

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Adverse Effects

• Maraviroc:

  • Common: Cough, fever, rash, upper respiratory tract infections, dizziness.

  • Serious: Hepatotoxicity (may present with allergic features), orthostatic hypotension, myocardial ischemia, postural dizziness.

• Plerixafor:

  • Common: Diarrhea, nausea, injection site reactions, headache, fatigue.

  • Serious: Splenic rupture (rare), thrombocytopenia, leukocytosis.

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Drug Interactions

• Maraviroc: Substrate of CYP3A4 and P-glycoprotein; requires dose adjustments with strong inhibitors (e.g., ketoconazole, ritonavir) or inducers (e.g., rifampicin).

• Plerixafor: Few significant CYP-mediated interactions; additive effects with other stem cell mobilizers.