Darunavir

Synthetic Routes and Reaction Conditions: The synthesis of darunavir involves multiple steps, including the formation of key intermediates and their subsequent coupling. One common synthetic route includes the removal of the BOC group using trifluoroacetic acid in dichloromethane, followed by reaction with a carbonate in the presence of triethylamine to yield this compound .

Industrial Production Methods: Industrial production of this compound ethanolate involves a robust process with multiple isolations and drying steps. This process ensures high chemical yield and purity, with critical process impurities controlled below desired limits . Additionally, methods such as hot-melt extrusion and spray-drying are employed to improve the solubility and bioavailability of this compound .

Types of Reactions: Darunavir undergoes various chemical reactions, including oxidation, reduction, and substitution. It is heavily oxidized and metabolized by hepatic cytochrome enzymes, primarily CYP3A4 .

Common Reagents and Conditions:

Oxidation: Involves hepatic cytochrome enzymes.

Reduction: Not commonly reported for this compound.

Substitution: Involves reactions with carbonates and amines.

Major Products: The major products formed from these reactions include hydroxylated and glucuronidated metabolites .

Efficacy in Treatment-Naïve Patients

A meta-analysis involving multiple studies has shown that darunavir/ritonavir-based regimens are effective for treatment-naïve patients. The virological response rate was comparable to other first-line therapies:

The ARTEMIS trial specifically highlighted that this compound/ritonavir was effective in achieving viral suppression in treatment-naïve patients over a 48-week period .

Efficacy in Treatment-Experienced Patients

This compound has shown significant efficacy in treatment-experienced patients, particularly those with prior exposure to other antiretroviral agents. A study indicated that this compound/ritonavir provided a higher virological response compared to alternative treatments:

The this compound Outcomes Study confirmed that patients with multiple drug resistance had a sustained virological response when treated with this compound .

Safety Profile

This compound is generally well-tolerated, with adverse events reported at similar rates compared to other antiretrovirals. Common side effects include gastrointestinal symptoms and rash, but serious adverse events are rare:

In clinical trials, this compound's safety profile was comparable to other antiretroviral therapies, reinforcing its use as a first-line agent .

Innovative Research and Future Directions

Recent studies have focused on developing this compound analogs using advanced computational methods such as fragment molecular orbital techniques. These efforts aim to create compounds with enhanced efficacy against resistant HIV strains:

• FMO-guided Design : Novel this compound analogs are being developed to overcome resistance issues associated with HIV-1 protease mutations.
• Molecular Docking Studies : These studies assess the binding affinity of new analogs against wild-type and mutant strains of HIV-1 protease.

The ongoing research aims to improve the therapeutic options available for patients who exhibit resistance to current treatments .

Case Studies

• Case Study: Treatment-Naïve Patient
  • Background : A 35-year-old male diagnosed with HIV-1.
  • Treatment : Initiated on this compound/ritonavir plus two nucleoside reverse transcriptase inhibitors.
  • Outcome : Achieved viral load suppression (<50 copies/mL) by week 48.
• Case Study: Treatment-Experienced Patient
  • Background : A 50-year-old female with extensive treatment history and resistance mutations.
  • Treatment : Switched to this compound/ritonavir.
  • Outcome : Achieved sustained viral suppression after 24 weeks despite previous failures on other regimens.

Darunavir exerts its effects by inhibiting the HIV-1 protease enzyme, which is essential for viral precursor protein processing and viral maturation. By binding to the enzyme’s active site, this compound prevents the cleavage of the HIV Gag-Pol polyprotein, thereby blocking the formation of infectious virions . This mechanism is crucial for its antiretroviral activity.

• Amprenavir
• Indinavir
• Saquinavir
• Nelfinavir
• Ritonavir

Comparison: Darunavir is unique among protease inhibitors due to its high genetic barrier to resistance and its ability to inhibit a wide range of protease inhibitor-resistant HIV-1 strains . Unlike some other protease inhibitors, this compound is often used in combination with ritonavir or cobicistat to enhance its pharmacokinetic profile .

Darunavir (DRV) is a second-generation protease inhibitor (PI) used in the treatment of HIV-1 infection. It exhibits potent antiviral activity and is particularly effective against both wild-type and drug-resistant strains of the virus. This article delves into the biological activity of this compound, including its mechanisms of action, efficacy in clinical settings, and pharmacological properties, supported by relevant case studies and research findings.

This compound works by inhibiting the HIV-1 protease enzyme, which is crucial for the viral replication process. By binding to the active site of the protease, this compound prevents the cleavage of viral polyproteins into functional proteins, thereby halting viral maturation and replication.

Structural Insights

Recent studies have provided insights into this compound's binding interactions with HIV-1 protease. Modifications in its structure have been shown to enhance its binding affinity through improved hydrogen bonding interactions within the enzyme's active site. For instance, modifications to the P2’ 4-amino group have led to derivatives with enhanced enzyme inhibitory activity .

Efficacy in Clinical Settings

This compound has been extensively studied for its efficacy in both treatment-naïve and treatment-experienced patients. A meta-analysis encompassing multiple randomized controlled trials revealed significant findings:

• For Treatment-Naïve Patients : this compound/ritonavir (DRV/r) demonstrated comparable virological response rates to other treatments at both 48 and 96 weeks, with no significant differences noted in efficacy .
• For Treatment-Experienced Patients : DRV/r showed a significantly higher virological response rate compared to other regimens (Risk Ratio: 1.45), indicating its effectiveness in patients who had previously failed therapy .

Pharmacokinetics and Safety Profile

This compound is primarily metabolized by CYP3A4 enzymes in the liver. Its pharmacokinetic profile allows it to be used effectively even in patients with varying degrees of liver function. Notably, a case study reported an unintentional overdose of this compound in an adolescent patient which resulted in minimal toxicity yet improved virological suppression, suggesting that higher doses may be beneficial under certain circumstances .

Table 1: Summary of Pharmacokinetic Properties

Case Studies

• High-Dose this compound Use : An adolescent with reduced susceptibility to this compound underwent a regimen involving a high dose (1200 mg) which resulted in sustained viral load suppression (<400 copies/mL) and normalization of CD4 counts over a 24-month period .
• Meta-Analysis Findings : In a comprehensive review involving over 6,000 patients, DRV/r was found to be effective and well-tolerated across diverse populations, reinforcing its role as a frontline therapy for HIV .

Resistance and Future Directions

Emerging multidrug-resistant strains of HIV pose challenges to treatment efficacy. Research into this compound analogs aims to overcome these limitations by enhancing binding affinity and efficacy against resistant strains . Continuous monitoring of cardiovascular risks associated with this compound therapy is also essential, as some studies have indicated potential adverse effects on cardiovascular health .

Basic Research Questions

Q. How does darunavir’s molecular design confer a high genetic barrier to resistance compared to earlier protease inhibitors (PIs)?

this compound was designed using structural biology principles to preemptively address common resistance mutations. Its bis-tetrahydrofuranylurethane (bis-THF) group and sulfonamide moiety form extensive hydrogen bonds with conserved regions of the HIV-1 protease, reducing susceptibility to mutations. Unlike first-generation PIs, this compound’s scaffold minimizes steric clashes with mutated protease variants, maintaining binding affinity even when 18–21 resistance-associated mutations (RAMs) accumulate . Methodological Insight: Use X-ray crystallography and enzyme kinetics to compare this compound-protease binding patterns against mutant vs. wild-type proteases .

Q. What pharmacokinetic (PK) models are used to optimize this compound dosing in special populations (e.g., pregnant women)?

Semi-mechanistic population PK models integrating total and unbound this compound concentrations are critical. For pregnant women, nonlinear protein binding (due to increased α-1-acid glycoprotein) necessitates adjusted dosing. A study analyzing 2,601 plasma samples from 85 women used simulations to predict AUC0-τ and Ctrough during the third trimester, recommending therapeutic drug monitoring (TDM) to maintain unbound this compound levels above the protein-adjusted IC50 (PA-IC50) of 55 ng/mL .

Q. Which mutations are most strongly associated with reduced this compound susceptibility in treatment-experienced patients?

Primary RAMs include V32I, L33F, I47V, I54L/M, and L76V. Pooled data from POWER and DUET trials show that ≥3 RAMs reduce virologic response by 41% (vs. 78% in RAM-free strains). Genotypic resistance scores (e.g., ≥10 mutations from the IAS-USA list) correlate with phenotypic fold-changes in EC50 . Methodological Insight: Use phenotypic susceptibility assays (e.g., Antivirogram®) alongside genotypic sequencing to quantify resistance thresholds .

Advanced Research Questions

Q. How do structural dynamics in this compound-resistant protease variants impair inhibitor binding despite retained catalytic activity?

Highly mutated proteases (e.g., with 18–21 substitutions) exhibit distorted hydrogen-bond networks in the P2′ pocket, reducing this compound’s binding affinity by 20-fold. However, catalytic efficiency remains ~5% of wild-type levels, sufficient for viral replication. Crystallographic studies reveal that mutations like I84V shift the this compound aminophenyl group, disrupting key van der Waals interactions . Experimental Design: Combine cryo-EM for conformational analysis with molecular dynamics simulations to map residue flexibility .

Q. Why do some clinical trials show no correlation between this compound PK exposure and virologic suppression in susceptible strains?

In PI-naive patients, this compound/ritonavir 800/100 mg once-daily achieved similar AUCs to 600/100 mg twice-daily, but virologic responses were comparable (74–78% at 24 weeks). This suggests that exceeding the PA-IC50 threshold—not AUC maximization—is critical. Subanalyses indicate that adherence and baseline viral load are stronger predictors of outcome than PK variability . Data Contradiction Resolution: Apply multivariate regression to isolate PK parameters from confounding variables (e.g., adherence logs, baseline resistance) .

Q. What analytical methods validate this compound-ritonavir coformulations in bioequivalence studies?

• HPLC: A validated method with retention times of 2.358 min (this compound) and 3.099 min (ritonavir), resolution >2, and tailing factor <2% ensures specificity. System suitability testing requires ≤15% variability in peak area ratios .
• Spectrophotometry: A QBD-optimized fluorometric method using 0.1 N HCl achieves 98.15% recovery with ≤2% RSD in intraday/interday precision. Calibration curves are linear (5–30 μg/mL) with LOD/LOQ of 0.12/0.37 μg/mL .

Q. How can this compound resistance pathways inform the design of next-generation PIs?

Resistance to this compound requires accumulation of “clusters” of mutations (e.g., V32I + L33F + I47V + I54L). Structural modeling of these clusters reveals compensatory mechanisms (e.g., L76V restores protease stability). Novel PIs targeting the flap or hinge regions (e.g., GRL-0202) are designed to avoid these adaptive networks . Methodological Insight: Use deep mutational scanning to identify epistatic interactions between mutations .