Dolutegravir

合成路线和反应条件： 多鲁特格拉韦的合成涉及多个步骤，从构建吡啶酮环开始。随后使用 3-®-氨基-1-丁醇进行环化，并进行一系列化学转化。 该过程可以通过连续流化学进行优化，显著缩短反应时间并提高产率 .

工业生产方法： 多鲁特格拉韦的工业生产通常采用高速均质和探头超声处理技术来制备纳米悬浮液。 这些方法提高了药物的溶解度和生物利用度，使其在治疗 HIV 阳性患者方面更有效 .

Hydrolysis

• Selective Monoester Hydrolysis :
  • Reagent : LiOH in THF/H₂O (4.5 hours, 72% yield) .
  • Optimization : KOH outperformed NaOH and TBAOH in selectivity .

Amidation

• Coupling Agents : Carbonyldiimidazole (CDI) facilitates amidation between carboxylic acid 4 and 2,4-difluorobenzylamine (10 ) .
• Yield Improvement : Flow conditions increased yield to 89% (vs. 33% in batch) by reducing side reactions .

Cyclization

• Reagent : (R)-3-Aminobutan-1-ol under acidic conditions (acetic acid) forms the oxazine ring .
• Byproduct Control : MgBr₂ promotes intramolecular cyclization, enhancing regioselectivity .

O-Debenzylation

• Reagent : Trifluoroacetic acid (TFA) at 39°C for 2 hours (90% yield) .

Demethylation

• Conditions : LiBr in THF at 100°C (31-minute residence time in flow) .
• Challenge : Elevated temperatures (>120°C) lead to elimination byproducts (e.g., 20 ) .

Metabolic Reactions of this compound

DTG undergoes three primary metabolic pathways :

• Plasma Half-Life : 15.6 hours, with 64% excreted in feces and 31.6% in urine .
• Drug Interactions : Minimal CYP3A4 induction/inhibition, but UGT1A1 inhibitors (e.g., atazanavir) may increase DTG exposure .

Stability and Byproduct Management

• Thermal Degradation : Demethylation at >120°C produces elimination byproducts; optimized flow conditions mitigate this .
• Oxidative Byproducts : Controlled using inert atmospheres during amidation and cyclization .

This synthesis and metabolic profile underscores this compound’s role as a second-generation HIV integrase inhibitor with a high genetic barrier to resistance .

Efficacy in Treatment-Naive Patients

Dolutegravir has demonstrated significant efficacy in treatment-naive individuals. Clinical trials such as SPRING-2 and SINGLE have shown that this compound-based regimens achieve viral suppression rates exceeding 90% within 48 weeks. These trials reported that a substantial proportion of participants achieved an undetectable viral load, defined as HIV-1 RNA <50 copies/mL.

Use in Treatment-Experienced Patients

This compound has also been effective in treatment-experienced patients, particularly those with resistance to other antiretrovirals. The VIKING studies assessed this compound's efficacy in patients with documented resistance to raltegravir or elvitegravir. Results indicated that a significant percentage of these patients achieved viral suppression after switching to this compound.

Pediatric Applications

Recent studies have explored this compound's potential for pediatric use. A study involving this compound-loaded chitosan nanoparticles aimed to enhance bioavailability for children infected with HIV. The formulation demonstrated improved pharmacokinetics compared to standard this compound, indicating promise for its use in younger populations.

Safety Profile and Adverse Effects

While this compound is generally well-tolerated, some adverse effects have been reported. Notably, psychiatric disorders have emerged as a concern in certain cases. A case report documented a patient experiencing severe psychiatric symptoms after switching to a this compound-based regimen, highlighting the need for careful monitoring.

Resistance and Long-Term Efficacy

Although this compound has a high genetic barrier to resistance, cases of emergent resistance have been documented, particularly in treatment-experienced patients with suboptimal adherence. A notable case from South Africa reported intermediate resistance to this compound after a patient failed to adhere to the prescribed regimen.

Case Study 1: Treatment-Experienced Patient

A 38-year-old woman with tuberculosis was switched to a regimen including this compound but failed to achieve viral suppression due to poor adherence and developed intermediate resistance.

Case Study 2: Psychiatric Symptoms

A 59-year-old woman developed severe psychiatric symptoms shortly after starting this compound, necessitating discontinuation of the drug and subsequent improvement within days.

多鲁特格拉韦通过与整合酶的活性位点结合来抑制 HIV-1 的复制。这阻止了逆转录病毒 DNA 整合到宿主细胞基因组中的链转移步骤，这是病毒复制所必需的。 通过阻断这一步骤，多鲁特格拉韦有效地抑制了病毒活性，降低了患者体内的病毒载量 .

类似化合物：

拉替格拉韦： 首个获批用于治疗 HIV 的整合酶抑制剂。

艾维格拉韦： 另一种需要药理增强剂的整合酶抑制剂。

比克格拉韦： 一种新型整合酶抑制剂，其疗效与多鲁特格拉韦相似。

卡博特格拉韦： 最近获批的具有长效制剂的整合酶抑制剂

多鲁特格拉韦的独特性： 多鲁特格拉韦以其高疗效、最少的药物相互作用以及无需药理增强剂即可给药而脱颖而出。 它还对一些对其他整合酶抑制剂有耐药性的 HIV 毒株保持活性，使其成为 HIV 治疗中宝贵的选择 .

Raltegravir: The first integrase inhibitor approved for HIV treatment.

Elvitegravir: Another integrase inhibitor that requires pharmacologic boosting.

Bictegravir: A newer integrase inhibitor with similar efficacy to Dolutegravir.

Cabotegravir: Recently approved integrase inhibitor with a long-acting formulation

Uniqueness of this compound: this compound stands out due to its high efficacy, minimal drug interactions, and ability to be administered without pharmacologic boosting. It also retains activity against some strains of HIV that are resistant to other integrase inhibitors, making it a valuable option in HIV treatment .

Dolutegravir (DTG) is a potent integrase strand transfer inhibitor (INSTI) that has been extensively studied for its efficacy in treating HIV-1 infection. This article delves into the biological activity of this compound, highlighting its pharmacological properties, resistance profiles, and clinical implications based on recent research findings.

This compound functions by inhibiting the integrase enzyme, which is crucial for the integration of viral DNA into the host genome. By binding to the integrase-DNA complex, this compound prevents the formation of the stable strand transfer complex necessary for viral replication. This mechanism is distinct from other antiretroviral drugs, allowing DTG to maintain efficacy against various resistant strains of HIV-1.

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties:

• Absorption : Rapidly absorbed with peak plasma concentrations reached within 2-3 hours post-ingestion.
• Half-life : Approximately 12 hours, permitting once-daily dosing without the need for pharmacokinetic enhancers.
• Metabolism : Primarily metabolized via hepatic glucuronidation (UGT1A1), with minimal renal excretion, making it suitable for patients with renal impairment .

Resistance Profile

This compound has demonstrated robust activity against various HIV-1 variants, including those resistant to other INSTIs like raltegravir. Key findings include:

• In vitro Activity : this compound retains activity against clinical isolates from patients who have failed raltegravir therapy. For instance, fold changes in susceptibility were observed as follows:
  • G140S + Q148H: Median FC-IC50 = 3.75 nM
  • G140S + Q148R: Median FC-IC50 = 13.3 nM
  • N155H: Median FC-IC50 = 1.37 nM .

The data suggests that this compound maintains near wild-type levels of activity against isolates with Y143 or N155H mutations, while susceptibility diminishes with the presence of multiple mutations at the Q148 position .

Efficacy in Clinical Studies

Clinical trials have established this compound's efficacy in diverse populations:

• Phase III Trials : Demonstrated superior virologic suppression compared to other antiretrovirals like efavirenz and rilpivirine.
• Pediatric Studies : A study involving children aged 4 weeks to less than 6 years indicated that a dispersible tablet formulation of this compound was well-tolerated and effective .

Case Studies

Several case studies illustrate this compound's clinical application:

• Case Study A : A patient with extensive drug resistance achieved viral suppression after switching to a this compound-based regimen, highlighting its efficacy in treatment-experienced individuals.
• Case Study B : In a cohort study involving pregnant women, this compound was associated with favorable maternal and neonatal outcomes without significant adverse effects .

Safety Profile

This compound has a favorable safety profile:

• Common adverse effects include insomnia and headache, but these are generally mild and manageable.
• Concerns regarding potential neural tube defects in early pregnancy have led to recommendations for alternative therapies during conception planning .

Future Directions

Research is ongoing to explore modified formulations of this compound aimed at enhancing its bioavailability and prolonging its action. One notable advancement is the development of a prodrug variant that significantly increases half-life and reduces clearance rates, showing promise in preclinical models .

Basic Research Questions

Q. What are the standard methodologies for assessing Dolutegravir's pharmacokinetic parameters in clinical studies?

• Methodological Answer : Pharmacokinetic studies typically employ serial blood sampling over 24 hours post-administration to measure parameters such as AUC (area under the curve), Cmax (maximum concentration), and trough levels. High-performance liquid chromatography (HPLC) or mass spectrometry is used for quantification. For example, studies in Black Southern African adults used this protocol to evaluate obesity's marginal impact on this compound exposure . Statistical analysis should include non-compartmental modeling to account for inter-individual variability.

Q. How are neuropsychiatric adverse effects (e.g., depression, insomnia) of this compound systematically evaluated?

• Methodological Answer : Meta-analyses of randomized controlled trials (RCTs) with Jadad scores ≥4 (indicating high quality) are standard. Studies like the neurotoxicity meta-analysis compared this compound with rilpivirine and efavirenz-based therapies, using standardized scales (e.g., PHQ-9 for depression) and adjusting for confounding variables such as prior psychiatric history . Subgroup analyses should exclude studies with efavirenz to isolate this compound-specific effects.

Q. What criteria guide this compound dosing in special populations (e.g., pregnant individuals, obese patients)?

• Methodological Answer : Dose adjustments are informed by pharmacokinetic studies measuring drug exposure in target populations. For example, a 24-hour pharmacokinetic study in obese patients (BMI ≥30 kg/m²) found no clinically significant exposure differences, supporting standard dosing . In pregnancy, prospective surveillance studies (e.g., Botswana’s Tsepamo study) monitor outcomes like neural tube defects (NTDs) to assess safety .

Advanced Research Questions

Q. How can researchers design multicohort studies to investigate this compound resistance in real-world settings?

• Methodological Answer : Collaborative designs (e.g., DTG RESIST study) integrate genotypic resistance tests and clinical data from observational cohorts. Key steps include:

• Cohort Selection : Enroll participants with virological failure (viral load >1,000 copies/mL) on this compound-based regimens.
• Data Harmonization : Standardize resistance mutation reporting (e.g., integrase mutations like R263K) and risk factors (e.g., NRTI resistance, subtype differences).
• Statistical Analysis : Use multivariable logistic regression to identify predictors (e.g., monotherapy, non-B subtypes) .

Q. How should contradictory findings on this compound-associated neurotoxicity be reconciled?

• Methodological Answer : Conduct sensitivity analyses to address heterogeneity. For example, the neurotoxicity meta-analysis found increased depression risk only when excluding efavirenz studies, highlighting the need to control for comparator therapies . Additional approaches:

• Mechanistic Studies : Explore this compound’s blood-brain barrier penetration via cerebrospinal fluid (CSF) pharmacokinetic sampling.
• Longitudinal Designs : Track neuropsychiatric symptoms over extended periods to distinguish transient vs. persistent effects.

Q. What strategies improve reproducibility in this compound pharmacokinetic studies across diverse populations?

• Methodological Answer : Implement protocol standardization:

• Sampling Intervals : Fixed timepoints (e.g., 0, 2, 4, 8, 24 hours post-dose).
• Analytical Validation : Cross-laboratory calibration of HPLC/mass spectrometry methods.
• Demographic Reporting : Include BMI, renal/hepatic function, and genetic factors (e.g., UGT1A1 polymorphisms affecting metabolism) .

Q. Contradiction Analysis

• Obesity vs. Dosing : While found no need for dose adjustment in obesity, prior hypotheses suggested altered drug distribution in adipose tissue. Researchers should validate findings in larger cohorts and diverse ethnicities .
• Subtype-Specific Resistance : highlights higher this compound resistance in non-B subtypes (e.g., CRF02_AG). This necessitates subtype-stratified analyses in clinical trials .