ラルテグラビル

Q1: How does Raltegravir exert its antiretroviral effect?

A1: Raltegravir is a potent inhibitor of HIV-1 integrase, specifically targeting the strand transfer step of the viral integration process. [] This prevents the integration of the viral genome into the host cell's DNA, a crucial step for viral replication. [, ]

Q2: What is the consequence of inhibiting HIV-1 integrase?

A2: Blocking the strand transfer step by Raltegravir leads to the accumulation of unintegrated viral DNA in the cytoplasm of infected cells. [, ] This ultimately prevents the production of new infectious viral particles, effectively suppressing viral replication. [, , ]

Q3: What is the significance of Raltegravir's target in the HIV life cycle?

A3: HIV-1 integrase is a viral enzyme essential for viral replication and is not found in human cells. [] Targeting this unique enzyme offers a high degree of selectivity, minimizing the potential for adverse effects on host cell processes. []

Q4: What is the molecular formula and weight of Raltegravir?

A4: This information is not provided in the provided scientific papers. Please consult comprehensive chemical databases like PubChem or DrugBank for detailed structural information.

Q5: How stable is Raltegravir under various storage conditions?

A5: While the provided research doesn't specify exact storage conditions, one study mentions that high-performance liquid chromatography (HPLC) was used to measure Raltegravir trough concentrations, suggesting it maintains stability in biological samples for analysis. [] Further research on its stability under different environmental conditions (temperature, humidity, light) would be valuable.

Q6: Does Raltegravir exhibit any catalytic activity itself?

A6: No, Raltegravir is an enzyme inhibitor. It acts by binding to HIV-1 integrase and blocking its catalytic activity, specifically the strand transfer reaction required for integrating viral DNA into the host cell genome. [, ]

Q7: Have any computational studies been conducted on Raltegravir?

A7: Yes, one study used an in vitro-in vivo extrapolation model to predict Raltegravir pharmacokinetics in virtual individuals with different gastrointestinal pH profiles. [] This model successfully predicted key pharmacokinetic variables with good accuracy compared to clinical data, demonstrating the utility of computational approaches in understanding Raltegravir disposition. []

Q8: How do structural modifications of Raltegravir affect its activity?

A8: The provided research focuses primarily on Raltegravir's clinical efficacy and resistance mutations rather than exploring detailed SAR. Investigating the impact of structural changes on Raltegravir's binding affinity, inhibitory potency, and resistance profile would be an interesting avenue for future research.

Q9: What is the primary route of Raltegravir elimination in humans?

A10: Raltegravir is primarily eliminated via metabolism, specifically through glucuronidation by the enzyme UGT1A1. [] This process leads to the formation of Raltegravir glucuronide, the major metabolite, which is then excreted in urine and feces. []

Q10: Does food intake affect Raltegravir pharmacokinetics?

A11: Yes, a study investigating the effect of different meal types on Raltegravir's pharmacokinetic profile found that high-fat meals might influence the drug's absorption and distribution without affecting overall exposure. [] This highlights the importance of understanding food-drug interactions for optimizing Raltegravir therapy.

Q11: How do Raltegravir concentrations vary across different biological compartments?

A12: Research indicates that Raltegravir concentrations can vary significantly between plasma, intracellular compartments (like peripheral blood mononuclear cells), and tissues (such as cervical tissue). [, ] These differences highlight the need to consider tissue-specific drug distribution when evaluating Raltegravir's efficacy and potential for pre-exposure prophylaxis (PrEP). []

Q12: What factors contribute to the high inter-individual variability observed in Raltegravir pharmacokinetics?

A12: Several factors can contribute to variability in Raltegravir's pharmacokinetic profile, including:

• Genetic polymorphisms: Variations in the UGT1A1 gene, particularly the UGT1A16 and 28 alleles, may impact Raltegravir metabolism and clearance. []
• Gastrointestinal factors: Luminal pH and the presence of divalent metals, like magnesium, can influence Raltegravir absorption. [, ]
• Co-administered medications: Drug-drug interactions with medications metabolized by UGT1A1 or those altering gastrointestinal pH can alter Raltegravir exposure. [, , , ]
• Liver transplantation: Patients who have undergone liver transplantation may experience reduced Raltegravir clearance, potentially leading to higher drug exposure. []

Q13: What is the significance of Raltegravir trough concentrations?

A14: Raltegravir's virologic efficacy is best correlated with its trough concentration (C trough). [] Maintaining C trough levels above the 95% inhibitory concentration (IC95) is crucial for achieving optimal viral suppression. [, ]

Q14: How is Raltegravir's efficacy assessed in preclinical settings?

A15: Cell-based assays using TZM-bl indicator cells are used to evaluate Raltegravir's ability to inhibit HIV infection in vitro. [] Additionally, humanized mouse models, such as the humanized BLT (bone marrow-liver-thymus) mice, are valuable tools for studying Raltegravir's antiviral activity, pharmacokinetics, and efficacy in preventing vaginal HIV transmission in vivo. []

Q15: Has Raltegravir's efficacy been demonstrated in clinical trials?

A16: Yes, numerous clinical trials have established the potent and durable antiretroviral activity of Raltegravir in both treatment-naive and treatment-experienced HIV-1-infected patients. [, , , , , , ] When combined with tenofovir/emtricitabine, Raltegravir achieves viral suppression and immune restoration comparable to efavirenz-based regimens. [, ] Moreover, Raltegravir has shown effectiveness in salvage therapy for patients with multidrug-resistant HIV-1 infection. [, , , ]

Q16: What are the primary mechanisms of resistance to Raltegravir?

A17: Resistance to Raltegravir typically arises from mutations in the HIV-1 integrase gene. [, , , ] The most common mutations associated with Raltegravir resistance cluster around three main pathways:

• N155 pathway: Mutations at position N155 (N155H/S) [, , ]

Q17: Does cross-resistance exist between Raltegravir and other integrase inhibitors?

A18: Yes, cross-resistance can occur between Raltegravir and other integrase strand transfer inhibitors (INSTIs), such as elvitegravir and dolutegravir. [, , ] The extent of cross-resistance depends on the specific mutations present in the HIV-1 integrase gene. [, , ] For instance, mutations in the Q148 pathway often confer a higher level of resistance to Raltegravir and elvitegravir compared to dolutegravir. [, ]

Q18: Can Raltegravir resistance impact subsequent treatment options?

A19: Yes, the emergence of Raltegravir resistance mutations can limit future treatment options, particularly with other INSTIs. [, ] Therefore, it's crucial to monitor for resistance development and consider alternative antiretroviral agents when appropriate.

Q19: Does Raltegravir retain any antiviral activity against resistant HIV-1 strains?

A20: Studies suggest that Raltegravir might have limited to no residual antiviral activity against HIV-1 strains harboring major resistance mutations. [, ] This finding raises questions about the benefit of maintaining Raltegravir in salvage regimens for patients with documented resistance. []