The synthesis of Maraviroc involves several steps. One method includes the “borrowing hydrogen” or “hydrogen autotransfer” method. This process involves the reaction of the tropane triazole with the (S)-amido alcohol, catalyzed by a suitable catalyst . Another method involves the preparation of a tropane derivative by reacting specific compounds under controlled conditions . Industrial production methods focus on optimizing the yield and purity of the final product through improved isolation and purification techniques .

Maraviroc undergoes various chemical reactions, including substitution and reduction reactions. Common reagents used in these reactions include hydrogen gas and suitable catalysts. The major products formed from these reactions are derivatives of the original compound, which may have different pharmacological properties .

HIV Treatment

Clinical Efficacy
Maraviroc was first approved for use in patients infected with R5-tropic HIV-1. In pivotal clinical trials such as the MOTIVATE 1 and MOTIVATE 2 studies, this compound demonstrated significant virologic efficacy when combined with optimized background antiretroviral regimens. After 48 weeks, patients treated with this compound showed greater reductions in HIV-1 RNA levels and increases in CD4+ T cell counts compared to placebo groups . Long-term safety evaluations have confirmed that this compound maintains its efficacy and safety profile over extended periods, with no new safety concerns reported through five years of follow-up .

Microbicide Development

Topical Applications
Recent studies have explored the potential of this compound as a topical microbicide to prevent HIV transmission. A notable study demonstrated that a topical gel formulation of this compound provided complete protection against vaginal HIV-1 challenges in humanized mouse models . This finding suggests that this compound could be a promising candidate for future microbicide clinical trials, especially in populations at high risk for HIV infection.

Reactivation of Latent HIV

Latency Reversal Agent
this compound has been investigated for its ability to reactivate latent HIV reservoirs, making it a candidate for use in "shock and kill" strategies aimed at eradicating HIV. In a clinical trial, this compound was shown to disrupt HIV latency in vivo through activation of NF-κB pathways, leading to increased viral expression in latent reservoirs . This application is critical for developing strategies to eliminate hidden viral reservoirs in patients undergoing antiretroviral therapy.

Neuroprotection

Inflammation Reduction
Research has indicated that this compound may exert neuroprotective effects by reducing inflammation associated with central nervous system infections. In vitro studies showed that this compound treatment significantly decreased nitric oxide production in astroglial cell cultures stimulated by pneumococcal bacteria, suggesting a potential role in mitigating neuroinflammation . This application could be relevant for managing neurological complications associated with HIV.

Cardiovascular Health

Impact on Arterial Stiffness
Emerging evidence suggests that this compound may improve cardiovascular health in individuals living with HIV. A study found that this compound treatment was associated with reduced arterial stiffness among patients receiving protease inhibitor-based antiretroviral therapy . This finding highlights the potential cardiovascular benefits of this compound, particularly in populations at risk for cardiovascular diseases due to chronic HIV infection.

Comprehensive Data Table

Maraviroc is an entry inhibitor that works by blocking HIV from entering human cells. Specifically, it is a selective, slowly reversible antagonist of the interaction between the human CCR5 receptor and the HIV-1 gp120 protein . By binding to the CCR5 receptor, this compound prevents the virus from attaching to and entering the host cell, thereby inhibiting viral replication .

Comparison with Similar Compounds

Mechanism of Action and Target Specificity

Maraviroc vs. Other Entry Inhibitors

This compound’s specificity for CCR5 contrasts with Plerixafor, a CXCR4 antagonist used for hematopoietic stem cell mobilization and CXCR4-tropic HIV . Dual antagonists like AMD3451 are investigational and may address dual/mixed-tropic HIV but lack clinical validation .

Efficacy Comparison with Efavirenz and Raltegravir

Table 1: Efficacy in Treatment-Naive Patients (5-Year Data)

This compound demonstrated non-inferiority to efavirenz (NNRTI) in the MERIT trial, with comparable virologic suppression and CD4+ recovery over 5 years . Both this compound and raltegravir (integrase inhibitor) show better tolerability than efavirenz, which is associated with neuropsychiatric adverse events .

Table 2: Adverse Event Rates (Pooled Clinical Trials)

This compound’s safety profile mirrors placebo in treatment-experienced patients, with lower hepatotoxicity and CNS toxicity compared to efavirenz .

Pharmacokinetics and Drug Interactions

Table 3: PK Parameters and Dose Adjustments

This compound’s PK is uniquely influenced by CYP3A4/Pgp activity. Co-administration with efavirenz (CYP3A4 inducer) reduces this compound AUC by 45%, necessitating a doubled dose (600 mg bid) . Conversely, potent CYP3A4 inhibitors (e.g., ritonavir) require a reduced dose (150 mg bid) .

Clinical Considerations

• Tropism Testing : Mandatory for this compound use, unlike other antiretrovirals .
• Drug Interactions : More complex than raltegravir but manageable with dose modulation .

Maraviroc (MVC) is a selective antagonist of the CCR5 chemokine receptor, primarily recognized for its role in the treatment of HIV-1 infection. As the first drug in its class approved by the U.S. Food and Drug Administration (FDA), this compound represents a significant advancement in antiretroviral therapy. This article explores the biological activity of this compound, including its mechanism of action, pharmacokinetics, clinical efficacy, and safety profile, supported by data tables and relevant case studies.

This compound functions by blocking the CCR5 receptor on CD4+ T cells, which HIV-1 uses to enter these cells. By preventing the binding of the viral envelope protein gp120 to CCR5, this compound inhibits the fusion of the viral membrane with the host cell membrane, thereby obstructing viral entry.

Key Findings on Mechanism:

• Inhibition Concentration : this compound demonstrated a geometric mean IC90 of 2.0 nM against 43 primary CCR5-tropic HIV-1 isolates .
• Resistance : It remains effective against viruses resistant to other drug classes, showing consistent sensitivity across 200 clinically derived pseudoviruses .

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties that support its clinical use.

Pharmacokinetic Profile:

Coadministration with food can affect absorption; for instance, a high-fat meal reduces Cmax and AUC by approximately 33% .

Clinical Efficacy

This compound has been evaluated in various clinical trials for its efficacy in treating HIV-1. It is particularly beneficial for patients with CCR5-tropic HIV strains.

Case Studies:

• Study on Treatment-Naive Patients : In a randomized controlled trial, this compound combined with other antiretrovirals showed superior virologic response compared to standard therapies in treatment-naive patients.
• Long-Term Efficacy : Longitudinal studies indicate that this compound maintains viral suppression over extended periods without significant resistance development .

Safety Profile

The safety profile of this compound is generally favorable, with no significant cytotoxicity reported in vitro.

Adverse Effects:

While this compound is well-tolerated, some adverse effects include:

• Common : Cough, fever, rash
• Serious : Hepatotoxicity and cardiovascular events have been noted but are rare .

Basic Research Questions

Q. What is the mechanistic basis of Maraviroc's antiviral activity, and how does CCR5 tropism influence treatment outcomes?

this compound inhibits HIV-1 entry by binding to the CCR5 coreceptor, preventing conformational changes required for viral fusion. Its efficacy is limited to CCR5-tropic (R5) viruses, as CXCR4- or dual-tropic variants evade this mechanism. Researchers must confirm viral tropism using assays like ultra-deep pyrosequencing (UDPS) or enhanced sensitivity Trofile™ before initiating therapy . Methodologically, tropism analysis should include genotypic/phenotypic testing and predictive algorithms (e.g., geno2pheno) to minimize false-positive rates .

Q. How should clinical trials for this compound be designed to account for treatment-experienced vs. naïve populations?

The MOTIVATE trials (phase 3) provide a template: double-blind, placebo-controlled studies with optimized background therapy (OBT) in treatment-experienced patients. Key design elements include:

• Stratification by baseline viral load and CD4 count.
• Exclusion of CXCR4-tropic viruses via tropism screening.
• Use of twice-daily dosing (300 mg) to account of CYP3A4-mediated drug interactions . For naïve populations, the MERIT trial highlights the importance of tropism reassessment over time due to potential coreceptor switching .

Q. What bioanalytical methods are validated for quantifying this compound in pharmacokinetic studies?

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the gold standard. Key validation steps include:

• Quadratic regression for calibration curves (1–10,000 ng/mL range).
• Use of ¹³C-isotope internal standards to mitigate matrix effects.
• Participation in external proficiency testing (e.g., CPQA initiatives) to ensure reproducibility .

Advanced Research Questions

Q. How do population pharmacokinetic (PK) models address variability in this compound exposure among diverse patient cohorts?

Semi-mechanistic PK models incorporate covariates like body weight, CYP3A4 activity, and drug-drug interactions (e.g., with ritonavir). For example:

• A two-compartment model with first-order absorption and linear elimination (CL = 58.5 L/hr) predicts exposure in healthy subjects.
• In treatment-experienced patients, nonlinear mixed-effects modeling (NONMEM/MONOLIX) accounts for sparse sampling and co-administered drugs . Discrepancies between sequential vs. simultaneous PK/PD modeling approaches should be evaluated using Akaike information criterion (AIC) .

Q. What methodologies reconcile contradictory findings between clinical trial and real-world efficacy data for this compound?

Retrospective cohort analyses suggest higher real-world efficacy due to newer OBT agents (e.g., integrase inhibitors). To resolve contradictions:

• Perform propensity score matching to control for baseline characteristics (e.g., prior drug resistance).
• Use time-to-event analyses (Cox regression) to adjust for confounding variables like adherence . Discordant results in MOTIVATE vs. MERIT trials highlight the impact of tropism assay sensitivity on patient selection .

Q. How does ultra-deep pyrosequencing (UDPS) improve predictive accuracy of this compound response compared to population sequencing?

UDPS detects minority CXCR4-tropic variants at frequencies as low as 0.3%, reducing false-negative tropism calls. Methodological steps include:

• Amplification of HIV-1 V3 loop regions with error-correcting PCR.
• Bioinformatics pipelines (e.g., Pyrotrop) to analyze sequence diversity and predict coreceptor usage.
• Specificity improves from 89% (population sequencing) to 99.4% (UDPS + Pyrotrop), minimizing virologic failure risk .

Q. What experimental strategies optimize this compound's efficacy in patients with evolving viral tropism?

Adaptive trial designs with serial tropism testing (e.g., every 12 weeks) are critical. Advanced approaches include:

• Dynamic PK/PD models integrating viral decay rates and CD4+ T-cell recovery.
• Combinatorial regimens with entry inhibitors (e.g., fostemsavir) to target dual/mixed-tropic reservoirs .

Q. Methodological Considerations

• Data Contradictions : Discrepancies between in vitro IC₅₀ values (3.3–7.2 nM) and clinical efficacy may arise from protein binding or compartmentalized replication. Use adjusted EC₉₀ values (≥100 nM) for in vivo extrapolation .
• Statistical Tools : Bayesian hierarchical models are recommended for meta-analyses of heterogeneous trial data (e.g., MOTIVATE subgroup analyses) .