Maraviroc (DB04835): A Comprehensive Monograph on a First-in-Class CCR5 Antagonist from HIV-1 Therapy to Broad-Spectrum Immunomodulation

1.0 Executive Summary

Maraviroc (DrugBank ID: DB04835) represents a significant milestone in the history of antiretroviral therapy (ART). As the first orally bioavailable small molecule antagonist of the C-C chemokine receptor type 5 (CCR5), its approval marked the introduction of a new class of HIV medications in over a decade.[1] Developed by Pfizer and marketed under the brand names Selzentry and Celsentri, Maraviroc introduced a novel mechanism of action that fundamentally differs from preceding antiretroviral agents. Instead of inhibiting viral enzymes once HIV has already infected a host cell, Maraviroc functions as an entry inhibitor, blocking the virus at the cell surface before infection can occur.[3]

The drug's primary clinical indication is for the treatment of human immunodeficiency virus type 1 (HIV-1) infection, but its use is highly specific. It is effective only against viral strains that utilize the CCR5 co-receptor for cellular entry, known as CCR5-tropic (or R5) virus.[1] This mechanistic specificity necessitates pre-treatment viral tropism testing, positioning Maraviroc as an early example of personalized medicine in infectious disease management.[6] Its clinical utility is most established in treatment-experienced patients with multidrug-resistant HIV, for whom it provides a new therapeutic option with no cross-resistance to other drug classes.[2]

Despite its innovative mechanism, the clinical application of Maraviroc is complex. Its metabolism is mediated almost exclusively by the cytochrome P450 3A4 (CYP3A4) enzyme system, making it highly susceptible to drug-drug interactions.[1] This metabolic vulnerability mandates a complicated, tiered dosing schedule (150 mg, 300 mg, or 600 mg twice daily) that is dictated entirely by the co-administration of CYP3A4-modifying medications.[10] Furthermore, Maraviroc carries a significant safety profile, highlighted by a U.S. Food and Drug Administration (FDA) black box warning for hepatotoxicity, which can be preceded by systemic allergic reactions.[6]

This report will demonstrate that the story of Maraviroc extends far beyond its role in HIV therapy. The CCR5 receptor is a key mediator of immune cell trafficking in a wide array of pathological processes. Consequently, Maraviroc's ability to block this pathway has propelled its investigation as a broad-spectrum immunomodulatory agent. Promising clinical and preclinical data are emerging for its use in diverse therapeutic areas, including graft-versus-host disease (GVHD) prophylaxis in transplant medicine, various oncologic indications where it disrupts the tumor microenvironment, and chronic inflammatory conditions such as non-alcoholic steatohepatitis (NASH) and atherosclerosis.[6] This monograph provides an exhaustive analysis of Maraviroc, covering its fundamental chemistry, its detailed pharmacology, its established role and regulatory journey in HIV management, and its promising future as a repurposed therapeutic for a range of human diseases.

2.0 Chemical Identity and Pharmaceutical Properties

This section delineates the fundamental chemical and physical characteristics of Maraviroc, which are foundational to its synthesis, formulation, and biological activity.

2.1 Identification and Nomenclature

Maraviroc is recognized globally by a consistent set of identifiers that ensure its unambiguous identification in scientific literature, regulatory filings, and clinical practice.

• Generic Name: The officially designated International Nonproprietary Name (INN) is Maraviroc.[6]
• Brand Names: The drug is marketed under two primary brand names, which vary by region. In the United States, it is sold as Selzentry®.[6] In the European Union and many other international markets, it is known as Celsentri®.[4]
• Database and Chemical Identifiers:
• DrugBank ID: DB04835.[1]
• CAS Number: 376348-65-1.[6]
• Developmental Code Name: During its development by Pfizer, Maraviroc was referred to by the code UK-427857.[6]
• Other Key Identifiers: It is cataloged in major chemical and biological databases, including PubChem (CID: 3002977), ChEMBL (ID: ChEMBL1201187), and has a Unique Ingredient Identifier (UNII: MD6P741W8A).[6]

2.2 Chemical Structure and Formula

The precise molecular structure of Maraviroc is critical to its function as a selective antagonist of the CCR5 receptor.

• Chemical Formula: The empirical formula for Maraviroc is C29​H41​F2​N5​O.[1]
• IUPAC Name: The systematic name according to the International Union of Pure and Applied Chemistry (IUPAC) is 4,4-Difluoro-N-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide.[6] Some sources provide a slightly different but equivalent nomenclature.[12]
• Structural Description: Chemically, Maraviroc is a complex small molecule belonging to several structural classes. It is characterized as a monocarboxylic acid amide, an azabicycloalkane, an organofluorine compound, and a member of the triazole family.[20] Its intricate architecture features a geminal difluorocyclohexyl carboxamide moiety linked to a β-amino acid derivative, which is in turn connected to a tropinone-type bicyclic system that is substituted with a 1,2,4-triazole ring.[24]
• Stereochemistry: The molecule possesses specific stereocenters that are essential for its high-affinity binding to the CCR5 receptor. These are defined by unique stereochemical identifiers, including its International Chemical Identifier (InChI) and its hashed InChIKey (GSNHKUDZZFZSJB-QYOOZWMWSA-N), which encode its three-dimensional structure.[6]

2.3 Physicochemical and Pharmaceutical Characteristics

The physical and chemical properties of Maraviroc influence its formulation, stability, and pharmacokinetic behavior.

• Molecular Weight: The calculated molecular weight is approximately 513.67 g/mol, often rounded to 513.7 Da in product literature.[19] Its precise monoisotopic mass is 513.327917369 Da.[1]
• Physical Form: In its pure state, Maraviroc is a white, crystalline solid.[12]
• Solubility: Maraviroc exhibits poor aqueous solubility, with a reported value of 1.06×10−2 g/L.[20] This property poses a challenge for oral absorption and is a key consideration in its pharmaceutical formulation. It is, however, soluble in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol, with reported solubilities up to 75 mM and 100 mM, respectively.[12]
• Formulations: To overcome its poor solubility and facilitate oral administration, Maraviroc is available in two main dosage forms:
• Film-coated tablets: These are available in multiple strengths, including 25 mg, 75 mg, 150 mg, and 300 mg. The tablets are characteristically blue, oval-shaped, and debossed with "MVC" followed by the dosage strength.[10]
• Oral solution: A 20 mg/mL liquid formulation is available, primarily for use in pediatric patients or adults who have difficulty swallowing tablets.[10]
• Stability and Storage: The compound is stable for at least four years when stored under appropriate conditions.[21] Storage recommendations for the pure chemical vary, with some sources suggesting refrigeration at +4°C, while others recommend long-term storage at -20°C.[19] The commercial tablet and solution formulations are stored at room temperature.[29]

Property	Value	Source(s)
Generic Name	Maraviroc	6
Brand Names	Selzentry (US), Celsentri (EU)	6
CAS Number	376348-65-1	6
Developmental Code	UK-427857	6
Chemical Formula	C29​H41​F2​N5​O	1
Molecular Weight	513.7 g/mol	20
Physical Form	White crystalline solid	20
Aqueous Solubility	1.06×10−2 g/L	20
Solubility in DMSO	Soluble to 75 mM	19
Formulations	Tablets (25, 75, 150, 300 mg), Oral Solution (20 mg/mL)	10
Table 1: Summary of Maraviroc Identifiers and Physicochemical Properties

3.0 Pharmacology

The pharmacological profile of Maraviroc is defined by its unique mechanism of action, its specific pharmacodynamic effects on the CCR5 receptor, and a complex pharmacokinetic profile that is central to its clinical management.

3.1 Mechanism of Action (MoA)

Maraviroc is the progenitor of a distinct class of antiretroviral drugs and its mechanism represents a paradigm shift from traditional intracellular viral targets.

• Drug Class: Maraviroc is classified as an HIV Entry and Fusion Inhibitor.[1] More specifically, it is a C-C Chemokine Receptor Type 5 (CCR5) Co-receptor Antagonist.[5]
• Molecular Target: The drug's sole pharmacological target is the human CCR5 receptor, a seven-transmembrane G-protein coupled receptor (GPCR). This receptor is naturally expressed on the surface of various immune cells, most notably CD4+ T-helper cells and macrophages, which are the primary targets of HIV.[1]
• Detailed Mechanism: Maraviroc functions as a selective, slowly reversible, small molecule antagonist.[1] Its mode of inhibition is that of a negative allosteric modulator.[6] This means that Maraviroc binds to a hydrophobic pocket within the transmembrane domains of the CCR5 receptor, a site distinct from where the natural chemokine ligands (like RANTES/CCL5) or the HIV envelope protein bind.[6] This allosteric binding event induces a conformational change in the extracellular loops of the CCR5 receptor. This altered shape makes the receptor unrecognizable to the HIV-1 surface glycoprotein gp120.[1] For CCR5-tropic (R5) strains of HIV-1, the interaction between gp120 and the CCR5 co-receptor is an obligatory second step, following the initial binding to the CD4 receptor, that triggers the conformational changes in the viral envelope necessary for membrane fusion and viral entry into the host cell.[4] By physically preventing this gp120-CCR5 association, Maraviroc effectively blocks the virus from entering the cell, thereby halting the viral life cycle before intracellular replication and integration can begin. This "outside-the-cell" mechanism is fundamentally different from that of reverse transcriptase, protease, and integrase inhibitors, which all act on intracellular stages of viral replication.[3]

3.2 Pharmacodynamics

The pharmacodynamic properties of Maraviroc are characterized by high potency and exquisite selectivity for its target, which in turn defines its spectrum of activity and clinical utility.

• Potency and Selectivity: Maraviroc exhibits potent antiviral activity against CCR5-tropic HIV-1 strains. It prevents the interaction between gp120 and CCR5 with a half-maximal inhibitory concentration (IC50​) as low as 6.4 nM in cell-based assays.[12] It is also a potent antagonist of the natural CCR5 ligands, inhibiting the binding of Macrophage Inflammatory Protein-1α (MIP-1α or CCL3), MIP-1β (CCL4), and RANTES (CCL5) with IC50​ values of 3.3 nM, 7.2 nM, and 5.2 nM, respectively.[21] This antagonism of natural chemokine signaling is the basis for its broader immunomodulatory potential.
• Tropic Specificity: The drug's efficacy is strictly limited to CCR5-tropic HIV-1. It demonstrates no clinically relevant activity against HIV-1 strains that use the alternative CXCR4 co-receptor (X4-tropic) or those that can use either co-receptor (dual/mixed-tropic), with IC50​ values for these strains exceeding 10 µM.[21] This high degree of selectivity is the biological basis for the mandatory requirement of a viral tropism test prior to initiating therapy, as administering the drug to a patient with non-R5 virus would be ineffective.[6]
• Cross-Resistance: A key advantage of Maraviroc, particularly for treatment-experienced patients, is its lack of cross-resistance with other established antiretroviral drug classes. Because it targets a host protein (CCR5) rather than a viral enzyme, mutations that confer resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), or integrase inhibitors (INSTIs) do not affect Maraviroc's activity. This makes it a valuable component of salvage therapy regimens for patients with extensive drug resistance.[2]

3.3 Pharmacokinetics (ADME Profile)

The absorption, distribution, metabolism, and excretion (ADME) profile of Maraviroc is complex and has profound implications for its clinical use, particularly regarding dosing and drug interactions.

• Absorption: Following oral administration, the absolute bioavailability of Maraviroc is dose-dependent, increasing from 23% for a 100 mg dose to a predicted 33% for a 300 mg dose.[1] Peak plasma concentrations ( Cmax​) are typically reached within 0.5 to 4 hours.[10] The absorption is influenced by food; co-administration of a 300 mg tablet with a high-fat breakfast was found to reduce both Cmax​ and the area under the curve (AUC) by 33%. This effect is even more pronounced with the oral solution.[1] Despite this, clinical trials demonstrating efficacy did not impose food restrictions, and the drug can be taken with or without food.[1]
• Distribution: Maraviroc distributes extensively into tissues, as indicated by its large apparent volume of distribution of approximately 194 L.[1] It is moderately bound (around 76%) to human plasma proteins, with affinity for both albumin and alpha-1 acid glycoprotein.[1]
• Metabolism: Maraviroc undergoes extensive metabolism, which is a critical determinant of its clinical pharmacology. In vitro and in vivo studies have unequivocally identified the cytochrome P450 (CYP) enzyme system as the primary metabolic pathway, with CYP3A4 being the major enzyme responsible for its clearance.[1] This heavy reliance on a single, highly inducible, and inhibitable enzyme pathway is the root cause of its numerous and clinically significant drug-drug interactions. The metabolism of Maraviroc primarily involves N-dealkylation to form a secondary amine, which is the most significant circulating metabolite but is pharmacologically inactive against HIV-1.[6]
• Excretion: The elimination of Maraviroc and its metabolites occurs predominantly through the feces (approximately 76% of a dose), with a secondary contribution from renal excretion in the urine (approximately 20%).[6] The terminal elimination half-life of the parent drug ranges from 14 to 18 hours, which supports a twice-daily dosing schedule to maintain therapeutic concentrations.[1]

The profound dependence of Maraviroc on CYP3A4 for its metabolism is not merely a pharmacokinetic detail; it is the single most important factor governing its practical clinical application. The FDA-approved label and international prescribing guidelines outline a complex, three-tiered dosing regimen for adults: 150 mg, 300 mg, or 600 mg twice daily.[10] This variation is not determined by patient characteristics like weight or disease severity, but is dictated exclusively by the presence of co-administered drugs that are known to be potent inhibitors or inducers of CYP3A4. For instance, when given with a potent CYP3A4 inhibitor like the protease inhibitor ritonavir, which blocks Maraviroc's metabolism and dramatically increases its concentration, the dose must be reduced to 150 mg twice daily to avoid toxicity. Conversely, when co-administered with a potent CYP3A4 inducer like the NNRTI efavirenz or the herbal supplement St. John's Wort, which accelerates its metabolism and lowers its concentration, the dose must be doubled to 600 mg twice daily to maintain efficacy.[1] This metabolic fragility places a significant burden on prescribers and pharmacists to conduct thorough medication reconciliation and makes Maraviroc a challenging agent to incorporate into the already complex polypharmacy regimens common in HIV treatment.

Parameter	Value	Source(s)
Oral Bioavailability	23% (100 mg dose) to 33% (300 mg dose)	1
Time to Peak Concentration (Tmax​)	0.5 - 4 hours	10
Volume of Distribution (Vd​)	~194 L	1
Plasma Protein Binding	~76%	1
Primary Metabolic Enzyme	Cytochrome P450 3A4 (CYP3A4)	1
Terminal Half-life (t1/2​)	14 - 18 hours	1
Primary Excretion Route	Feces (~76%), Urine (~20%)	6
Table 2: Summary of Key Pharmacokinetic Parameters for Maraviroc

4.0 Clinical Application in HIV-1 Management

The clinical use of Maraviroc is highly specific, guided by its unique mechanism and supported by data from pivotal clinical trials that have defined its role in the landscape of antiretroviral therapy.

4.1 Approved Indications and Limitations of Use

Maraviroc is approved by regulatory agencies, including the U.S. FDA and the European Medicines Agency (EMA), for a well-defined patient population.

• Indication: Maraviroc is indicated for use in combination with other antiretroviral agents for the treatment of adults and pediatric patients (weighing at least 2 kg) who are infected with only CCR5-tropic HIV-1.[1]
• Limitation of Use: The prescribing information explicitly states that Maraviroc is not recommended for patients with dual/mixed- or CXCR4-tropic HIV-1.[1] This limitation is a direct consequence of its mechanism of action; since the drug only blocks the CCR5 co-receptor, it is ineffective against viral strains that can use the CXCR4 co-receptor for entry. Efficacy was not demonstrated in a Phase 2 study of this patient population.[8]

4.2 The Critical Role of Tropism Testing

A unique and mandatory prerequisite for prescribing Maraviroc is the determination of the patient's viral tropism.

• Requirement for Testing: Before initiating therapy, all patients must undergo a viral tropism test using a blood sample to confirm that their HIV-1 strain is exclusively CCR5-tropic.[4]
• Assay Sensitivity: The FDA label and other guidelines emphasize the need for a highly sensitive and validated tropism assay, such as the Trofile assay used in the pivotal trials.[7] This is because virologic failure on Maraviroc has been associated with the outgrowth of pre-existing, low-level CXCR4- or dual/mixed-tropic viral populations that were not detected by less sensitive screening methods.[6] The tropism test result directly dictates whether a patient is a candidate for the drug. A result of "R5" indicates the virus uses CCR5 and Maraviroc can be used, while a "non-R5" or "non-reportable" result precludes its use.[4]

4.3 Dosage and Administration

The dosing of Maraviroc is complex and requires careful consideration of concomitant medications, patient age and weight (for pediatrics), and renal function.

• General Administration: Maraviroc is administered orally twice daily. The tablet formulation may be taken with or without food.[1]
• Adult Dosing: The standard adult dose is determined by co-administered drugs that interact with the CYP3A4 metabolic pathway:
• 150 mg twice daily: Used when co-administered with potent CYP3A inhibitors (e.g., most protease inhibitors, ketoconazole, clarithromycin).[8]
• 300 mg twice daily: This is the standard dose when taken with drugs that do not significantly induce or inhibit CYP3A4 (e.g., NRTIs, raltegravir, enfuvirtide).[8]
• 600 mg twice daily: Required when co-administered with potent CYP3A inducers (e.g., efavirenz, etravirine, rifampin, carbamazepine, St. John's Wort).[8]
• Pediatric Dosing: For children aged 2 years and older and weighing at least 10 kg, dosing is based on body weight (or body surface area in some studies) and the same categories of concomitant medications. Both the oral solution and tablets are used, and the dose must not exceed the recommended adult dose for the corresponding interacting drug class.[10]
• Renal Impairment: Dose adjustments or contraindications are required for patients with impaired renal function, particularly those with a creatinine clearance (CrCl) below 30 mL/min. The recommendations are complex and depend on the specific combination of renal function and concomitant CYP3A-modifying drugs.[8]

4.4 Pivotal Clinical Trial Evidence

The clinical efficacy and safety of Maraviroc were established in a series of large, randomized, controlled Phase III trials.

• MOTIVATE 1 & 2 Trials (Treatment-Experienced Patients): These two identical, placebo-controlled trials were the cornerstone for Maraviroc's initial approval.[3] The studies enrolled highly treatment-experienced patients with documented resistance to multiple antiretroviral classes and confirmed CCR5-tropic virus. Patients were randomized to receive an optimized background therapy (OBT) based on resistance testing, plus either placebo or Maraviroc (once or twice daily). The results at 48 weeks were definitive:
• Virologic Suppression: Approximately 60% of patients in the twice-daily Maraviroc arm achieved a viral load of less than 400 copies/mL, compared to only 26% in the placebo arm. For the more stringent endpoint of <50 copies/mL, about 45% of the twice-daily Maraviroc group succeeded, approximately doubling the rate seen with placebo.[6]
• Immunologic Response: Patients receiving Maraviroc experienced significantly greater immunologic recovery, with a mean increase in CD4+ cell counts of 106 cells/μL in the twice-daily group, compared to only 56 cells/μL in the placebo group.[6]
• MERIT Trial (Treatment-Naive Patients): This trial was designed to evaluate Maraviroc as part of an initial treatment regimen. It compared a regimen of Maraviroc plus zidovudine/lamivudine (ZDV/3TC) against a standard-of-care regimen of efavirenz plus ZDV/3TC in treatment-naive patients with R5-tropic virus.[9] The results were more nuanced and ultimately shaped Maraviroc's clinical positioning:
• Virologic Efficacy: At 48 weeks, 65% of patients in the Maraviroc arm achieved a viral load <50 copies/mL, compared to 69% in the efavirenz arm. Although the rates were numerically similar, the statistical analysis failed to demonstrate that Maraviroc was non-inferior to efavirenz based on the pre-specified margin.[34]
• Immunologic Benefit: Despite the non-inferiority failure on the primary endpoint, the Maraviroc arm showed a statistically significant greater mean increase in CD4+ cells (170 vs. 143 cells/mm³).[34]
• Resistance and Failure: A critical finding was that more patients in the Maraviroc arm experienced virologic failure and, importantly, developed resistance to the background NRTIs (lamivudine) compared to the efavirenz arm.[26]

The conflicting data from the MERIT trial had a lasting impact on Maraviroc's place in therapy. The failure to definitively prove non-inferiority in viral suppression against a well-established first-line agent like efavirenz was a significant hurdle. For a chronic, lifelong infection like HIV, durable and robust viral suppression is the paramount goal of therapy. Any uncertainty regarding this primary endpoint makes a drug less favorable for initial treatment. This was compounded by the concerning signal of increased development of resistance to the background drugs in the Maraviroc arm. This suggested that if a Maraviroc-based initial regimen failed, it could compromise future treatment options, a critical consideration in long-term HIV management. While the superior CD4+ cell recovery was an intriguing finding, potentially pointing to unique immunologic benefits, it was not sufficient to outweigh the concerns about virologic efficacy and resistance. Consequently, despite receiving approval for treatment-naive patients in the U.S., Maraviroc never became a preferred or recommended first-line agent. Its role was largely cemented as a valuable, but niche, drug for treatment-experienced patients with limited options due to resistance, as demonstrated unequivocally in the MOTIVATE trials.

Trial	Patient Population	Study Arms	% with VL <50 copies/mL (48w)	Mean CD4+ Increase (cells/μL) (48w)	Key Safety/Resistance Findings
MOTIVATE 1 & 2	Treatment-Experienced	1. OBT + Placebo 2. OBT + Maraviroc 150 mg BID	~23% ~45%	56 106	No major safety differences vs. placebo. Virologic failure sometimes associated with tropism shift to CXCR4.
MERIT	Treatment-Naive	1. EFV + ZDV/3TC 2. Maraviroc 300 mg BID + ZDV/3TC	69% 65%	143 170	Failed to meet non-inferiority for virologic suppression. Higher rate of virologic failure and resistance to background NRTIs in Maraviroc arm.
Table 4: Summary of Efficacy and Safety Outcomes from Pivotal Phase III Trials (MOTIVATE 1 & 2, MERIT)

5.0 Safety, Tolerability, and Risk Management

The use of Maraviroc requires careful monitoring and risk management due to a profile of potentially serious adverse reactions, common side effects, and a high potential for drug-drug interactions.

5.1 Boxed Warning: Hepatotoxicity

The most significant safety concern associated with Maraviroc is the risk of liver injury, which prompted the U.S. FDA to issue a boxed warning, its strongest form of safety alert.

• Warning Details: The label warns of hepatotoxicity, which has been reported in patients taking Maraviroc.[5]
• Associated Allergic Features: Crucially, the development of liver injury may be preceded by evidence of a systemic allergic reaction. These prodromal symptoms can include a severe or pruritic (itchy) rash, fever, peripheral eosinophilia (an increase in a type of white blood cell), and/or elevated serum immunoglobulin E (IgE) levels.[26]
• Clinical Management: Patients should be instructed to stop taking Maraviroc and seek immediate medical evaluation if they develop signs of hepatitis, such as jaundice (yellowing of the skin or eyes), dark or tea-colored urine, vomiting, or pain in the upper right quadrant of the abdomen.[29] Special caution and enhanced monitoring are recommended when administering Maraviroc to patients with pre-existing liver dysfunction or those co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).[3]

5.2 Other Serious Adverse Reactions

Beyond hepatotoxicity, several other serious adverse events require clinical vigilance.

• Severe Skin and Hypersensitivity Reactions: Potentially life-threatening skin reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), have been reported.[5] These hypersensitivity reactions can involve rash, fever, and multi-organ dysfunction, including hepatic failure. The development of any signs or symptoms of a severe skin or hypersensitivity reaction warrants immediate discontinuation of Maraviroc and other suspected agents.[6]
• Cardiovascular Events: In the pivotal MOTIVATE trials involving treatment-experienced patients, a higher number of cardiovascular events, specifically myocardial ischemia and/or infarction, were observed in patients receiving Maraviroc compared to those receiving placebo.[5] Consequently, the label advises using Maraviroc with caution in patients who are at increased risk for cardiovascular events.[26]
• Postural Hypotension: Maraviroc can cause a drop in blood pressure upon standing (postural or orthostatic hypotension), leading to symptoms of dizziness and lightheadedness. This risk may be exacerbated in patients with underlying renal impairment or those taking other medications that lower blood pressure.[29]

5.3 Common Adverse Reactions

The most frequently reported adverse events associated with Maraviroc vary depending on the patient population being studied.

• In Treatment-Experienced Adults (MOTIVATE trials): The most common adverse events that occurred at a higher frequency with Maraviroc than with placebo included cough, pyrexia (fever), upper respiratory tract infections, rash, musculoskeletal symptoms, and dizziness.[4]
• In Treatment-Naive Adults (MERIT trial): The most common adverse events occurring more frequently in the Maraviroc arm compared to the efavirenz arm included upper respiratory tract infections, bronchitis, and various gastrointestinal complaints such as flatulence, bloating, and distention.[10]
• In Pediatric Patients: In studies of treatment-experienced children and adolescents, the most common adverse reactions (≥3% incidence) were primarily gastrointestinal, including vomiting, abdominal pain, diarrhea, and nausea, as well as dizziness.[10]

5.4 Drug-Drug Interactions

As a substrate of CYP3A4, Maraviroc is subject to numerous clinically significant drug-drug interactions that can alter its plasma concentration, necessitating dose adjustments to maintain safety and efficacy.[1]

• CYP3A4 Inhibitors (Increase Maraviroc Levels): Co-administration with potent CYP3A4 inhibitors can significantly increase Maraviroc concentrations, raising the risk of adverse effects. Key interacting drugs in this class include:
• Antiretrovirals: Most protease inhibitors (e.g., atazanavir, darunavir, ritonavir), cobicistat, elvitegravir.[1]
• Antifungals: Ketoconazole, itraconazole, voriconazole.[1]
• Antibiotics: Clarithromycin, telithromycin.[1]
• Other: Cyclosporine, diltiazem, verapamil.[1]
• CYP3A4 Inducers (Decrease Maraviroc Levels): Co-administration with potent CYP3A4 inducers can accelerate Maraviroc metabolism, leading to sub-therapeutic concentrations and risking virologic failure. Key interacting drugs include:
• Antiretrovirals: Efavirenz, etravirine.[1]
• Anticonvulsants: Carbamazepine, phenytoin, phenobarbital.[1]
• Antimycobacterials: Rifampin, rifabutin.[1]
• Herbal Supplements: St. John's Wort (Hypericum perforatum) is a potent inducer and its use should be avoided.[1]

5.5 Contraindications

In addition to the warnings and precautions, there are specific situations where the use of Maraviroc is contraindicated.

• Hypersensitivity: The drug is contraindicated in patients with a known hypersensitivity to Maraviroc or any of its excipients. Notably, some tablet formulations contain soya lecithin, making them contraindicated for patients with allergies to peanut or soya.[8]
• Severe Renal Impairment with Interacting Drugs: The most critical contraindication applies to patients with severe renal impairment (CrCl < 30 mL/min) or end-stage renal disease (ESRD) who are concurrently receiving potent CYP3A inhibitors or inducers. In this population, the combination of impaired renal clearance and altered metabolism makes it impossible to achieve safe and effective drug exposures through dose adjustment.[8]

Concomitant Drug/Class	Example Drugs	Effect on Maraviroc	Recommended Adult Maraviroc Dose	Source(s)
Potent CYP3A Inhibitors	Ritonavir, Ketoconazole, Clarithromycin, Itraconazole	Increase plasma concentration	150 mg twice daily	8
Potent CYP3A Inducers	Efavirenz, Rifampin, Carbamazepine, St. John's Wort	Decrease plasma concentration	600 mg twice daily	1
Non-Interacting Drugs	NRTIs, Raltegravir, Enfuvirtide, Tipranavir/ritonavir	No significant effect	300 mg twice daily (Standard Dose)	8
Table 5: Clinically Significant Drug-Drug Interactions and Recommended Dose Adjustments

6.0 Regulatory History and Global Access

The journey of Maraviroc from a laboratory discovery to a globally available medication involved key regulatory milestones in the United States and Europe, which have defined its approved uses and availability.

6.1 Development and FDA Approval (Selzentry)

Maraviroc was discovered and developed by Pfizer, representing a novel approach to HIV treatment. Its path to market in the U.S. was facilitated by regulatory mechanisms designed to expedite access to important new therapies.

• Discovery and Development: The compound, originally designated UK-427857, was discovered by Pfizer scientists at their research facility in Sandwich, UK, in 1997.[3]
• Regulatory Timeline:
• February 2007: The New Drug Application (NDA) for Maraviroc was granted accelerated regulatory review status by the U.S. Food and Drug Administration (FDA), recognizing its potential to address an unmet medical need.[40]
• April 2007: The FDA's Antiviral Drugs Advisory Committee unanimously recommended accelerated approval for Maraviroc for use in treatment-experienced patients with multidrug-resistant HIV.[6]
• August 6, 2007: The FDA granted full approval for Selzentry (maraviroc) for use in combination with other antiretrovirals for treatment-experienced adults infected with only CCR5-tropic HIV-1.[3] This approval was a landmark event, making Maraviroc the first oral medication in a new class of HIV drugs to be approved in more than a decade.[3] The approval was based on 24-week data from the MOTIVATE trials, with a requirement for longer-term data to be submitted for traditional approval.[3]
• November 2016: The FDA expanded the indication for Selzentry to include pediatric patients, specifically children and adolescents weighing at least 2 kg.[10]

6.2 EMA Marketing Authorisation (Celsentri)

Shortly after its U.S. approval, Maraviroc received marketing authorisation in the European Union, though with some key differences in its initial approved labeling.

• Approval Date: The European Commission granted a centralized marketing authorisation for Celsentri (maraviroc) valid throughout the European Union on September 18, 2007.[6]
• Initial Indication: The initial EU approval was for treatment-experienced adult patients infected with only CCR5-tropic HIV-1, in combination with other antiretrovirals.[9] A notable difference from the U.S. was that Celsentri was not initially licensed for use in treatment-naive patients in Europe.[9] This decision likely reflected the European regulators' interpretation of the MERIT trial data, where Maraviroc failed to meet the non-inferiority endpoint against efavirenz.
• Indication Expansion: Over time, the European indication was broadened to align more closely with the U.S. approval, and now includes treatment-experienced adolescents and children from 2 years of age and weighing at least 10 kg.[32]
• Generic Availability: The patent protection for the innovator product has since allowed for the introduction of generic versions. For example, Maraviroc Amarox has been approved in the European Economic Area (EEA) through a decentralised procedure after demonstrating bioequivalence to the reference product, Celsentri, thereby increasing access and potentially reducing costs.[42]

7.0 Investigational Uses and Future Directions

The therapeutic story of Maraviroc is evolving significantly beyond its initial indication for HIV-1. Its fundamental mechanism—blocking the CCR5 chemokine receptor—targets a pivotal pathway in immune cell trafficking that is implicated in a wide range of human diseases. This has opened a vast field of investigation for drug repurposing. The fact that Maraviroc has a well-characterized safety and tolerability profile from over a decade of clinical use in HIV provides a substantial advantage, de-risking and potentially accelerating its development for new indications.[13] This exploration is not a series of disconnected efforts but a logical, mechanism-driven expansion of the drug's core immunomodulatory function. The CCR5 receptor's role in directing the migration of T-lymphocytes and macrophages to sites of inflammation or tissue damage is the common thread linking its potential use in disparate fields like transplant medicine, oncology, and chronic inflammatory diseases.[12]

7.1 Immunomodulation in Graft-versus-Host Disease (GVHD)

One of the most advanced investigational uses for Maraviroc is in the prevention of GVHD, a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT).

• Rationale: GVHD is driven by alloreactive donor T-cells migrating to and attacking host tissues such as the skin, gut, and liver. The CCR5 receptor and its ligands are crucial for orchestrating this lymphocyte recruitment.[45] The central hypothesis is that blocking CCR5 with Maraviroc could prevent immune cell infiltration into target organs, thereby mitigating GVHD without compromising the beneficial graft-versus-tumor (GVT) effect needed to eliminate the underlying malignancy.[45]
• Evidence and Outcomes: A series of Phase I/II clinical trials have provided compelling evidence supporting this hypothesis.[6]
• Adding Maraviroc to standard GVHD prophylaxis regimens (e.g., tacrolimus and methotrexate) was found to be safe and feasible in high-risk patients undergoing allo-HCT.[47]
• Treatment resulted in a remarkably low incidence of acute GVHD, with a particularly strong protective effect against visceral GVHD of the gut and liver, which are the most severe forms.[45]
• An extended 90-day course of Maraviroc was shown to be superior to a shorter 30-day course, leading to a significantly improved GVHD-free, relapse-free survival (GRFS) and better overall survival.[48]
• Pharmacokinetic analyses from these trials suggest a dose-response relationship, with higher trough concentrations of Maraviroc being associated with a lower incidence of acute GVHD, highlighting the importance of achieving adequate drug exposure.[48]

7.2 Repurposing in Oncology

The CCL5/CCR5 signaling axis is increasingly recognized as a key player in cancer progression. It facilitates not only the metastasis of CCR5-expressing tumor cells but also, critically, the recruitment of immunosuppressive cells like regulatory T-cells (Tregs) and tumor-associated macrophages (TAMs) into the tumor microenvironment (TME). This creates a protective, immunosuppressive niche that allows the tumor to evade immune surveillance. Maraviroc's ability to disrupt this axis is the foundation for its investigation as an anti-cancer agent.[12]

• Preclinical and Early Clinical Evidence:
• Colorectal Cancer (CRC): Maraviroc has completed Phase I/II trials in patients with CRC liver metastasis.[13] Preclinical studies show it can inhibit the accumulation of cancer-associated fibroblasts and reduce the extent of peritoneal disease and tumor burden in animal models.[13]
• Breast Cancer: In vitro and in vivo models have shown that Maraviroc can block the metastasis of aggressive basal-like breast cancer cells and reduce the growth of metastatic tumors in the lungs.[12]
• Gastric Cancer: Studies demonstrate that CCR5 antagonism with Maraviroc reduces gastric cancer cell migration and adhesion, effectively decreasing dissemination in mouse models.[46]
• Hodgkin Lymphoma: Maraviroc has shown significant promise in this malignancy. It reduces tumor cell growth, inhibits the accumulation of monocytes that form the supportive TME, and, importantly, acts synergistically with standard-of-care chemotherapies like doxorubicin and brentuximab vedotin, potentially allowing for more effective and less toxic combination regimens.[51]
• Hepatocellular Carcinoma (HCC): In a mouse model of diet-induced liver disease, Maraviroc was shown to prevent the development of HCC by suppressing the pro-tumorigenic activity of macrophages and liver progenitor cells.[53]

7.3 Emerging Therapeutic Areas

The immunomodulatory effects of Maraviroc are being explored in a growing list of other conditions characterized by chronic inflammation or immune dysregulation.

• Non-alcoholic Steatohepatitis (NASH): The progression from simple fatty liver (steatosis) to the inflammatory state of NASH and subsequent fibrosis is driven by immune cell infiltration. The MASH trial (Maraviroc Add-on for Steatohepatitis in HIV) was a UK-based, proof-of-concept study designed to assess whether 48 weeks of Maraviroc treatment could reduce liver inflammation and fibrosis in HIV-positive patients with biopsy-confirmed NASH.[14] The rationale is that CCR5 antagonism could directly inhibit the inflammatory processes driving liver damage.[13]
• Atherosclerosis and Cardiovascular Risk: Chronic inflammation is a key driver of atherosclerosis. Completed Phase 4 trials have investigated Maraviroc's potential to modulate atherosclerosis in HIV patients, a population with elevated cardiovascular risk.[11] Small pilot studies have suggested that Maraviroc treatment can improve measures of endothelial function and reduce markers of arterial stiffness and atherosclerotic burden.[61]
• Long COVID (Post-Acute Sequelae of SARS-CoV-2 Infection): Persistent, dysregulated inflammation is hypothesized to be a major contributor to Long COVID symptoms. A Phase 2 clinical trial is currently recruiting patients to investigate Maraviroc as part of a combination antiviral regimen, likely targeting the chronic inflammatory component of the condition.[62]
• Neuropathic Pain: Preclinical research in rat models has shown that Maraviroc can produce antinociceptive (pain-relieving) effects. This is thought to be mediated by modulating the inflammatory state of glial cells (microglia and astroglia) in the central nervous system.[12]
• HIV Pre-Exposure Prophylaxis (PrEP): Given its entry-inhibiting mechanism, Maraviroc has been explored as a potential agent for PrEP. Completed Phase 1 trials have evaluated its safety and pharmacokinetics for this purpose, both as an oral agent and as part of a long-acting vaginal ring in combination with other antiretrovirals like Dapivirine.[21]

Therapeutic Area	Rationale for Use	Highest Phase of Development	Key Findings / Status	Source(s)
Graft-vs-Host Disease (GVHD)	Blocks migration of alloreactive T-cells to host tissues.	Phase II	Reduced incidence of acute visceral GVHD; improved GVHD-free and overall survival with extended 90-day course.	6
Colorectal Cancer	Inhibits fibroblast accumulation and metastasis.	Completed Phase I/II	Efficacy demonstrated in animal models of liver metastasis.	13
Hodgkin Lymphoma	Disrupts tumor microenvironment; synergizes with chemotherapy.	Preclinical	Reduced tumor growth and monocyte infiltration in xenografts; synergistic with doxorubicin.	51
NASH (in HIV patients)	Reduces hepatic inflammation and fibrosis progression.	Phase IV (Proof-of-Concept)	The MASH trial investigated changes in liver histology after 48 weeks of treatment.	14
Atherosclerosis (in HIV patients)	Modulates vascular inflammation.	Completed Phase IV	Pilot studies suggest improved endothelial function and reduced atherosclerotic burden.	11
Long COVID	Targets persistent inflammation.	Phase II (Recruiting)	Investigating Maraviroc as part of a combination antiviral therapy.	62
HIV Pre-Exposure Prophylaxis (PrEP)	Blocks viral entry at the point of transmission.	Completed Phase I	Safety and PK evaluated for oral and vaginal ring formulations.	63
Table 6: Overview of Key Investigational Uses for Maraviroc

8.0 Synthesis and Concluding Remarks

Maraviroc holds a unique and dichotomous position in modern pharmacology. On one hand, it is a highly effective but clinically complex antiretroviral agent, confined to a specific niche within HIV-1 management. On the other, it is emerging as a promising immunomodulatory drug with a remarkable breadth of potential applications that span oncology, transplant medicine, and chronic inflammatory diseases. This dual identity is not a contradiction but rather a direct consequence of its precise and powerful mechanism of action.

As an antiretroviral, Maraviroc's legacy is that of a trailblazer. It validated a novel therapeutic strategy: blocking viral entry by targeting a host co-receptor. This provided a crucial new option for patients with extensive drug resistance, offering hope where few alternatives existed. However, the very specificity of its action—its sole efficacy against CCR5-tropic virus—and the complexities arising from its CYP3A4-dependent metabolism have prevented it from becoming a mainstream, first-line agent. The mandatory tropism testing and the intricate, interaction-driven dosing schedule demand a high level of clinical vigilance, cementing its role as a specialized tool rather than a universal solution.

Yet, the true future of Maraviroc may lie far beyond the field of virology. The key insight is that the CCR5 receptor is not merely a doorway for HIV; it is a master regulator of immune cell trafficking. The pathological infiltration of T-cells and macrophages is a common mechanistic thread in the progression of cancer, the tissue damage of GVHD, the fibrosis of NASH, and the inflammation of atherosclerosis. The ability of Maraviroc to block this fundamental process is the unifying principle that makes its repurposing a logical and compelling scientific endeavor.

The progress in these investigational areas is significant. The compelling Phase II data in GVHD prophylaxis suggest a potential new standard of care for transplant recipients. The extensive preclinical evidence in oncology highlights a strategy to dismantle the tumor's protective microenvironment, turning "cold" tumors "hot" and making them more susceptible to both chemotherapy and immunotherapy. The ongoing trials in NASH and Long COVID address major unmet medical needs driven by chronic inflammation.

The path forward is not without challenges. Translating the promise of these early-phase and preclinical studies into approved indications will require large, expensive, and well-designed randomized controlled trials. Furthermore, managing its complex drug interaction profile will remain a critical consideration as it is studied in combination with diverse therapeutic agents in different patient populations. Nevertheless, the opportunity is profound. Maraviroc's established safety profile from more than fifteen years of clinical use provides an invaluable foundation, significantly de-risking and accelerating its journey through clinical development for new indications.

In conclusion, Maraviroc is a quintessential example of how a deep and nuanced understanding of a molecular pathway can unlock therapeutic potential far beyond its original target. It has evolved from a targeted weapon against a single virus to a potential platform therapeutic for a host of human diseases unified by the common mechanism of pathological inflammation. The next chapter in the story of Maraviroc will be defined by its journey to realize this broader immunomodulatory promise, potentially transforming the treatment landscape for some of our most challenging medical conditions.

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