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Lenacapavir API Manufacturers & Suppliers

General Description:

Lenacapavir, identified by CAS number 2189684-44-2, is a notable compound with significant therapeutic applications. HIV/AIDS remains an area of concern despite the introduction of numerous successful therapies, mainly due to the emergence of multidrug resistance and patient difficulty in adhering to treatment regimens. Lenacapavir is a first-in-class capsid inhibitor that demonstrates picomolar HIV-1 inhibition as a monotherapy _in vitro_, little to no cross-resistance with existing antiretroviral agents, and extended pharmacokinetics with subcutaneous dosing. Lenacapavir was first globally approved on August 22, 2022 by the European Commission to treat adults with multi-drug resistant HIV infection. On December 22, 2022, it was also approved by the FDA.

Indications:

This drug is primarily indicated for: Lenacapavir, in combination with other antiretroviral(s), is indicated for the treatment of multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults who are experiencing a failure of their current antiretroviral regimen due to resistance, intolerance, or safety considerations. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lenacapavir undergoes metabolic processing primarily in: Metabolism played a lesser role in lenacapavir elimination. It undergoes CYP3A4- and UGT1A1-mediated oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation. The metabolites of lenacapavir have not been fully characterized. No single circulating metabolite accounted for >10% of plasma drug-related exposure. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lenacapavir are crucial for its therapeutic efficacy: Following subcutaneous administration, lenacapavir is slowly released but completely absorbed, with peak plasma concentrations occurring at 84 days post-dose. Absolute bioavailability following oral administration is low, approximately 6 to 10%. T_max after oral administration is about four hours. The mean steady-state C_max (%CV) is 97.2 (70.3) ng/ mL following oral and subcutaneous administration. According to population pharmacokinetics analysis, lenacapavir exposures (AUC_tau, C_max and C_trough) were 29% to 84% higher in heavily treatment-experienced patients with an HIV-1 infection compared to subjects without an HIV-1 infection. A low-fat meal had negligible effects on drug absorption. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lenacapavir is an important consideration for its dosing schedule: The median half-life ranged from 10 to 12 days following following oral administration, and 8 to 12 weeks following subcutaneous administration. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lenacapavir exhibits a strong affinity for binding with plasma proteins: _In vitro_, lenacapavir is approximately 99.8% bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lenacapavir from the body primarily occurs through: Following a single intravenous dose of radiolabelled-lenacapavir in healthy subjects, 76% of the total radioactivity was recovered from feces and less than 1% from urine. Unchanged lenacapavir was the predominant moiety in plasma (69%) and feces (33%). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lenacapavir is distributed throughout the body with a volume of distribution of: The steady state volume of distribution was 976 L in heavily treatment-experienced patients with an HIV-1 infection. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lenacapavir is a critical factor in determining its safe and effective dosage: Lenacapavir clearance was 3.62 L/h in heavily treatment experienced patients with HIV-1 infection. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lenacapavir exerts its therapeutic effects through: Lenacapavir is an antiviral drug with an extended pharmacokinetic profile. Lenacapavir works against the HIV-1 virus by inhibiting viral replication: it interferes with a number of essential steps of the viral lifecycle, including viral uptake, assembly, and release. Single subcutaneous doses ≥100 mg in healthy volunteers resulted in plasma concentrations exceeding the 95% effective concentration (EC₉₅) for ≥12 weeks while doses ≥300 mg exceeded the EC₉₅ for ≥24 weeks. In treatment-naive HIV-1-infected patients, a single subcutaneous dose of 20-450 mg resulted in a mean maximum log₁₀-transformed reduction in plasma HIV-1 RNA of 1.35-2.20 by the ninth-day post-injection. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lenacapavir functions by: HIV-1 co-opts various host factors during its replicative cycle, including during host cell entry, nuclear integration, replication, and virion assembly. Following the initial fusion with the host cell membrane, the viral capsid is released into the host cell cytoplasm. The capsid comprises approximately 250 hexamers and exactly 12 pentamers, each composed of monomeric capsid proteins (CA). Each CA monomer has an N-terminal and C-terminal domain (NTD/CTD) and offers an interaction surface for host cell machinery. Several important protein-protein interaction interfaces occur between CA monomers in the assembled multimers; the binding constants of these proteins are substantially lower for assembled multimers than individual capsid monomers. To facilitate HIV-1 genomic integration, the capsid must cross the nuclear envelope, for which it utilizes the nuclear pore complex (NPC). Two host proteins shown to be essential for capsid nuclear entry that directly bind to the capsid are cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and nucleoporin 153 (Nup153, an NPC protein present on the nucleoplasmic face of the complex). Both proteins bind the same phenylalanine-glycine binding pocket between the NTD and CTD of neighbouring CA monomers in multimeric CA assemblies. Lenacapavir contains a difluorobenzyl ring that occupies the same binding pocket as CPSF6/Nup153, overlapping with the benzyl group of F321 in CPSF6 and F1417 in Nup153 in the overlayed structures. Crystal structures of lenacapavir bound to CA hexamers reveal that six lenacapavir molecules bind to each hexamer, establishing extensive hydrophobic interactions, two cation-π interactions, and seven hydrogen bonds, contacting ~2,000 Ų of buried protein surface area. Strong binding of lenacapavir, therefore competitively interrupts capsid interactions with CPSF6 and Nup153. _In vitro_ HIV-1 replication inhibition experiments in a variety of cell lines show EC₅₀ values of ~12-314 pM, with greater efficacy against early steps over later steps. At very low concentrations (0.5 nM), lenacapavir inhibits viral nuclear entry, while at higher concentrations (5-50 nM), it additionally inhibits viral DNA synthesis and reverse transcription. As CPSF6 and Nup153 are essential for nuclear entry, it is likely that lenacapavir binding inhibits these interactions and blocks capsid nuclear entry. Lenacapavir may have additional effects beyond blocking interactions with host cell factors. Lenacapavir increases the rate and extent of CA assembly, dramatically extends the lifetime of assembled CA structures, even at high salt concentrations, and alters assembled capsid morphology. The stabilizing concentration is ~1:1, closely mimicking the observed binding stoichiometry to isolated CA hexamers. Further analysis suggests that lenacapavir binding alters intra- and inter-hexamer interactions, altering the structure and stability of the resulting assemblies. Serial passage of HIV-1 in increasing concentrations of lenacapavir resulted in the appearance of major resistance mutations Q67H and N74D, which remain sensitive to other antiretroviral drugs. Extended passage resulted in the additional mutations L56I, M66I, K70N, N74S, and T107N. All identified resistance mutations map to the lenacapavir binding site, and all but the Q67H variant show reduced replication capacity _in vitro_. Additional studies have shown no lenacapavir resistance in variants associated with resistance to other antiretrovirals or naturally occurring polymorphisms, suggesting a very low potential for cross-resistance in combination therapy. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Lenacapavir is categorized under the following therapeutic classes: Anti-HIV Agents, Antiinfectives for Systemic Use, Antiviral Agents, Antivirals for Systemic Use, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (moderate), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Direct Acting Antivirals, Heterocyclic Compounds, Fused-Ring, P-glycoprotein substrates, Pyrazoles, UGT1A1 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.