Bictegravir

Bictegravir can be synthesized through a multi-step process involving several intermediates. One method involves the preparation of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide or its pharmaceutically acceptable salts . Another method involves a continuous three-step synthetic strategy that optimizes solvents, temperature, and times to achieve better yields and lower costs .

Table 1: Key Synthetic Steps and Conditions

• Critical Steps :
  • Enzymatic Reduction : The stereoselective reduction of 3-carbonylcyclopentanecarboxylic acid to (3R)-3-hydroxycyclopentanecarboxylic acid ensures correct chirality for subsequent steps .
  • Azide Cyclization : Forms the bicyclic oxazepine core under mild conditions, avoiding racemization .
  • Final Coupling : HATU-mediated amide bond formation between the oxazepine intermediate and 2,4,6-trifluorobenzylamine achieves the target structure .

Metabolic Reactions

This compound undergoes hepatic and renal metabolism primarily via enzymatic oxidation and glucuronidation.

Table 2: Metabolic Pathways and Enzymatic Targets

• Key Findings :
  • CYP3A4 Inhibition : Co-administration with CYP3A4 inhibitors (e.g., macrolides) increases this compound exposure, necessitating dose adjustments .
  • UGT1A1 Polymorphism : Reduced glucuronidation efficiency in patients with UGT1A1*28 alleles may prolong half-life .

Stability and Degradation

This compound demonstrates pH-dependent stability and susceptibility to photodegradation.

Table 3: Stability Under Controlled Conditions

• Formulation Stability : Recrystallization from methanol or N-methyl-2-pyrrolidone/water yields >99.5% pure product .

Drug-Drug Interaction Chemistry

Efficacy in Clinical Trials

Phase 3 Studies
Bictegravir has been evaluated in several Phase 3 clinical trials. In these studies, it demonstrated non-inferiority compared to other standard regimens, such as dolutegravir combined with emtricitabine and tenofovir alafenamide. For instance, one study reported that after 96 weeks, 84% of participants on this compound achieved an HIV-1 RNA level of less than 50 copies/mL, comparable to 86% in the dolutegravir group .

Long-Term Effectiveness
The BICSTaR (this compound Single Tablet Regimen) study provides real-world evidence supporting the long-term effectiveness of this compound. Data from this observational cohort study showed that after 12 months of treatment, HIV-1 RNA was suppressed to less than 50 copies/mL in 94% of treatment-naïve participants and 97% of treatment-experienced participants .

Safety Profile

This compound's safety profile has been extensively documented. In clinical trials, drug-related adverse events were reported in approximately 20% of participants receiving this compound, which is lower compared to the dolutegravir group where adverse events were reported in about 28% . The most common side effects included gastrointestinal issues and headache, with serious adverse events being rare .

Real-World Applications

Diverse Populations
Research indicates that this compound is effective across diverse populations. A study focusing on Asian cohorts found that after 12 months of treatment with this compound/emtricitabine/tenofovir alafenamide, 98.2% of treatment-naïve participants achieved viral suppression . This highlights this compound's applicability in various demographic groups.

Combination Therapies
this compound is also being explored in combination with other antiretroviral therapies for enhanced efficacy. For example, ongoing research into nanoparticle formulations combining this compound with tenofovir alafenamide aims to develop long-acting formulations that could improve adherence and outcomes in HIV prevention strategies .

Case Studies

Case Study: BICSTaR Study
In the BICSTaR study involving over 1500 participants from multiple countries, researchers assessed the effectiveness and safety of this compound/emtricitabine/tenofovir alafenamide. The results confirmed high rates of viral suppression and favorable tolerability over a year-long follow-up period .

Case Study: Long-Acting Formulations
A novel approach using a nanoformulation combining this compound with tenofovir alafenamide has shown promise in preclinical studies for long-acting HIV prevention. This formulation aims to provide sustained drug release, potentially reducing the frequency of dosing required for effective prophylaxis against HIV .

Bictegravir inhibits the strand transfer of viral DNA into the human genome by targeting the HIV-1 integrase enzyme. This prevents the integration of the HIV-1 virus into the host DNA, thereby blocking the replication and propagation of the virus . This compound has shown powerful antiviral activity against various subtypes of HIV-1 and HIV-2 in vitro .

Bictegravir belongs to the class of integrase strand transfer inhibitors, which also includes dolutegravir, cabotegravir, elvitegravir, and raltegravir . Compared to these compounds, this compound has unique pharmacokinetic and pharmacodynamic properties, such as a long plasma half-life and minimal drug-drug interactions . This compound, dolutegravir, and raltegravir are recommended components of initial regimens for most people with HIV in the US adult and adolescent HIV treatment guidelines .

Bictegravir (BIC) is an integrase strand transfer inhibitor (INSTI) utilized in the treatment of HIV-1 infection. It is part of the combination therapy Biktarvy, which includes emtricitabine (FTC) and tenofovir alafenamide (TAF). BIC exhibits high potency and selectivity against HIV-1, demonstrating a favorable pharmacokinetic profile and resistance characteristics compared to other INSTIs like raltegravir (RAL) and elvitegravir (EVG) .

This compound functions by inhibiting the HIV integrase enzyme, which is crucial for the viral replication cycle. Specifically, BIC binds to the integrase active site, blocking the strand transfer step necessary for viral DNA integration into the host genome. This action effectively halts viral replication and contributes to viral load reduction in patients .

Key Features of this compound's Mechanism:

• High Potency : BIC shows superior antiviral activity against multiple HIV-1 variants.
• Resistance Profile : It has a longer dissociation half-life from integrase/DNA complexes than RAL and EVG, making it less susceptible to resistance mutations .
• Synergistic Activity : In vitro studies indicate that BIC, when combined with FTC and TAF, exhibits synergistic anti-HIV activity without antagonism .

Pharmacokinetics

This compound is characterized by its favorable pharmacokinetic properties:

• Bioavailability : High oral bioavailability allows for once-daily dosing.
• Half-life : Extended half-life supports sustained antiviral effects.
• Drug Interactions : BIC is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), necessitating caution when co-administered with drugs that inhibit these transporters .

Table 1: Pharmacokinetic Parameters of this compound

Clinical Efficacy

Clinical trials have demonstrated that this compound-containing regimens are highly effective in achieving viral suppression in both treatment-naïve and treatment-experienced patients.

Case Studies

• Long-term Efficacy in Women and Older Adults :
  • A study highlighted that long-term use of B/F/TAF resulted in significant immune recovery among women and individuals aged 60 and over, with high efficacy rates maintained over time .
• Nanoencapsulation Study :
  • Research indicated that nanoencapsulation of BIC plus TAF improved intracellular concentrations of the drug, enhancing its therapeutic effectiveness against HIV .

Safety Profile

The safety profile of this compound is generally favorable, with no significant overlapping toxicities observed when used in combination with FTC and TAF. Studies indicate no evidence of genotoxicity or carcinogenicity associated with this compound, further supporting its clinical use .

Common Adverse Effects:

• Gastrointestinal disturbances
• Fatigue
• Headache

Basic Research Questions

Q. What experimental models are most appropriate for evaluating bictegravir’s efficacy against HIV-1 in mucosal tissue?

Methodological Answer: Non-human primate (NHP) models are critical for studying this compound’s mucosal penetration and efficacy, as human trials cannot directly measure drug concentrations in penile, rectal, or urethral tissues. Use high-performance liquid chromatography (HPLC) or mass spectrometry to quantify this compound levels in mucosal swabs and correlate them with viral suppression rates in NHPs. Include control groups receiving emtricitabine/tenofovir to isolate this compound’s contribution .

Q. How does this compound’s antiviral activity profile compare to dolutegravir in INSTI-resistant HIV-1 strains?

Methodological Answer: Conduct in vitro susceptibility assays using patient-derived HIV-1 isolates with integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs). Measure fold-change (FC) in EC50 values relative to wild-type virus for both drugs. Focus on mutations like G140S/Q148R/H/K, where this compound shows greater conformational flexibility and slower dissociation from the integrase-DNA complex compared to dolutegravir. Use statistical tools (e.g., ANOVA) to validate potency differences .

Q. What pharmacokinetic (PK) parameters should be prioritized when designing studies on this compound in obese populations?

Methodological Answer: Use physiologically based pharmacokinetic (PBPK) modeling to predict AUC (area under the curve) and trough concentrations (Cτ) in obese vs. non-obese cohorts. Validate models with sparse sampling in clinical trials, focusing on tissue distribution and protein-binding differences. Monitor viral suppression rates to assess clinical relevance of PK changes .

Advanced Research Questions

Q. How can researchers resolve contradictions between in vitro and clinical data on this compound’s efficacy against INSTI-resistant variants?

Methodological Answer: Perform systematic reviews of in vitro selection studies (e.g., VIKING trial data) and real-world clinical outcomes. Use meta-analysis to quantify discrepancies, such as higher failure rates in patients with Q148 + ≥2 RAMs despite favorable in vitro this compound activity. Investigate confounding factors like adherence, drug-drug interactions, and host genetics .

Q. What experimental designs optimize this compound dosing for event-driven HIV prevention strategies?

Methodological Answer: Design randomized crossover trials comparing steady-state vs. on-demand this compound dosing in NHPs. Measure drug concentrations in mucosal tissues and plasma at multiple timepoints. Pair with ex vivo challenge assays using HIV-1 pseudoviruses to model prevention efficacy. Employ Bayesian adaptive designs to refine dosing intervals .

Q. How do this compound’s pharmacodynamic properties influence combination therapy outcomes in patients with pre-existing M184V/I mutations?

Methodological Answer: Retrospectively analyze clinical trial data (e.g., FDA submission studies) to compare viral suppression rates in patients with M184V/I receiving this compound/emtricitabine/tenofovir vs. dolutegravir-based regimens. Use deep sequencing to detect emergent INSTI RAMs and quantify viral fitness costs. Apply logistic regression to identify predictors of virologic failure .

Q. What methodologies best assess this compound’s penetration into immune sanctuaries (e.g., lymph nodes, CNS)?

Methodological Answer: Use radiolabeled this compound in animal models to track tissue distribution via PET-CT imaging. Corrogate findings with LC-MS/MS measurements in biopsy samples. For human studies, pair lumbar punctures (for CSF) and fine-needle aspirates (lymph nodes) with population PK modeling to estimate compartment-specific exposure .

Guidance for Formulating Rigorous Research Questions

• PICO Framework : Structure questions around Population (e.g., INSTI-experienced patients), Intervention (this compound dosing), Comparison (dolutegravir), and Outcome (virologic failure rate) .
• FINER Criteria : Ensure questions are Feasible (e.g., accessible biospecimens), Novel (e.g., mucosal PK in underrepresented populations), and Relevant to NIH HIV Cure research priorities .