Raltegravir potásico
Descripción general
Descripción
Raltegravir Potasio: es un medicamento antirretroviral que se utiliza principalmente para el tratamiento de la infección por el VIH-1. Es la forma de sal potásica de raltegravir, que es un inhibidor de la transferencia de la hebra de la integrasa del VIH. Este compuesto fue el primero de su clase en ser aprobado por la Administración de Alimentos y Medicamentos (FDA) de EE. UU. en 2007 . Raltegravir Potasio funciona inhibiendo la enzima integrasa, que es esencial para el proceso de replicación viral .
Aplicaciones Científicas De Investigación
Treatment of HIV Infection
Raltegravir potassium is indicated for the treatment of HIV-1 infection in both adults and pediatric patients. Its use is essential in achieving viral suppression when combined with other antiretroviral agents. The drug's mechanism involves inhibiting the integrase enzyme, which is crucial for viral replication.
Efficacy in Clinical Trials
Significant clinical trials have demonstrated the efficacy of raltegravir. For instance, in the BENCHMRK studies, patients treated with raltegravir showed a higher percentage of achieving viral loads below 50 copies/mL compared to those receiving placebo. Specifically, at week 156, 51% of patients on raltegravir achieved this milestone versus only 22% in the placebo group . Furthermore, after 240 weeks, the mean increase in CD4 cell counts was notable, indicating robust immune recovery among those treated with raltegravir .
Pharmacokinetics and Dosage
Raltegravir potassium is administered orally, typically at a dosage of 400 mg twice daily. It exhibits a favorable pharmacokinetic profile, with peak plasma concentrations reached approximately three hours post-dose. The drug shows dose-proportional absorption and does not significantly prolong the QTc interval, making it a safe option for many patients .
Table: Pharmacokinetic Parameters of Raltegravir
| Parameter | Value |
|---|---|
| Tmax | ~3 hours |
| AUC (Area Under Curve) | Dose-proportional |
| Cmax | Increases with dose |
Safety Profile and Side Effects
The safety profile of raltegravir potassium has been evaluated extensively. Common side effects include gastrointestinal disturbances and rash; however, severe adverse events are rare. Monitoring for hypersensitivity reactions and liver function is recommended during treatment .
Combination Therapy
Raltegravir is often used in combination with other antiretroviral drugs to enhance treatment efficacy and reduce the risk of resistance development. This combination approach is crucial for achieving sustained virologic suppression.
Case Study: Efficacy in Treatment-Naïve Patients
In a cohort study involving treatment-naïve patients, those receiving a regimen including raltegravir showed significantly improved outcomes compared to traditional therapies. The study reported that after 48 weeks, over 80% of participants achieved undetectable viral loads .
Potential Beyond HIV Treatment
Recent research suggests that raltegravir may have applications beyond HIV treatment. Investigations into its effects on other viral infections and its potential role in cancer therapy are ongoing. For example, studies are exploring how integrase inhibitors like raltegravir may influence cellular mechanisms relevant to oncogenesis .
Mecanismo De Acción
Raltegravir Potasio inhibe la enzima integrasa del VIH, evitando la integración del ADN viral en el genoma de la célula huésped. Esta inhibición bloquea la replicación del virus, lo que reduce la carga viral en el cuerpo del paciente. El compuesto se metaboliza principalmente mediante glucuronidación .
Métodos De Preparación
Rutas sintéticas y condiciones de reacción: La síntesis de Raltegravir Potasio implica varios pasos, incluida la N-metilación selectiva de un intermedio de pirimidona. El proceso generalmente incluye los siguientes pasos :
N-alquilación: El intermedio de pirimidona se alquila utilizando (clorometil)dimetilclorosilano y fluoruro de potasio.
Amidación: El producto alquilado se somete a amidación con una amina.
Desililación: El paso final implica la desililación utilizando fluoruro de potasio en metanol.
Métodos de producción industrial: La producción industrial de Raltegravir Potasio implica técnicas de granulación en seco para preparar comprimidos comprimidos. El proceso incluye mezclar raltegravir con excipientes, comprimir la mezcla para formar pastillas, dimensionar las pastillas para formar gránulos y finalmente comprimir los gránulos en comprimidos .
Análisis De Reacciones Químicas
Tipos de reacciones: Raltegravir Potasio sufre varios tipos de reacciones químicas, que incluyen:
Oxidación: Puede oxidarse en condiciones específicas.
Reducción: Puede reducirse utilizando agentes reductores apropiados.
Sustitución: Pueden ocurrir varias reacciones de sustitución, particularmente involucrando el grupo fluorofenilo.
Reactivos y condiciones comunes:
Oxidación: Los agentes oxidantes comunes incluyen peróxido de hidrógeno y permanganato de potasio.
Reducción: Se pueden utilizar agentes reductores como borohidruro de sodio.
Productos principales: Los principales productos formados a partir de estas reacciones dependen de los reactivos y las condiciones específicas utilizados. Por ejemplo, la oxidación puede producir derivados hidroxilados, mientras que la reducción puede producir compuestos desoxigenados .
Comparación Con Compuestos Similares
Raltegravir Potasio se compara con otros inhibidores de la integrasa del VIH como:
- Elvitegravir
- Dolutegravir
- Bictegravir
Singularidad: Raltegravir Potasio fue el primer inhibidor de la integrasa aprobado para uso clínico, sentando un precedente para los fármacos posteriores de esta clase. Es conocido por su acción rápida y su eficacia para reducir la carga viral .
Compuestos similares:
- Elvitegravir : Otro inhibidor de la integrasa con mecanismos similares pero diferentes propiedades farmacocinéticas.
- Dolutegravir : Conocido por su mayor barrera a la resistencia en comparación con Raltegravir.
- Bictegravir : Ofrece dosificación una vez al día y se utiliza a menudo en terapias combinadas .
Actividad Biológica
Raltegravir potassium is an antiretroviral medication primarily used in the treatment of HIV-1 infection. As the first integrase strand transfer inhibitor (INSTI), it functions by inhibiting the integrase enzyme, which is crucial for the viral replication process. This article explores the biological activity of raltegravir potassium, including its pharmacokinetics, mechanisms of action, efficacy in clinical studies, and safety profile.
Raltegravir inhibits the strand transfer activity of the HIV integrase enzyme. By doing so, it prevents the integration of viral DNA into the host cell genome, thereby blocking the replication cycle of HIV-1. This mechanism is vital for managing HIV infections, especially in patients with strains resistant to other antiretroviral therapies .
Pharmacokinetics
Absorption and Distribution:
- Raltegravir is rapidly absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 4 hours post-dose.
- It has a high plasma protein binding rate (approximately 83%) and shows extensive distribution throughout the body, with significant concentrations found in gastrointestinal organs and excretion pathways .
Metabolism:
- The primary metabolic pathway for raltegravir involves glucuronidation, primarily mediated by UGT1A1, with minor contributions from UGT1A9 and UGT1A3. This metabolic pathway results in a major metabolite that is less pharmacologically active than the parent compound .
Excretion:
- Raltegravir is excreted mainly through feces and urine. Studies have shown that it crosses the placenta and is present in breast milk, indicating potential implications for pregnant or lactating individuals .
Efficacy in Clinical Studies
Raltegravir has been evaluated in multiple clinical trials demonstrating its effectiveness in reducing viral loads and increasing CD4 cell counts among HIV-infected patients.
Key Findings from Clinical Trials:
- BENCHMRK Studies: In these randomized trials involving treatment-experienced patients, raltegravir showed a significant reduction in viral load compared to placebo. At week 156, 51% of patients on raltegravir achieved viral loads under 50 copies/mL versus only 22% in the placebo group .
| Study Duration | Raltegravir Group (%) | Placebo Group (%) |
|---|---|---|
| Week 156 | 51% < 50 copies/mL | 22% < 50 copies/mL |
| Week 240 | 42% < 50 copies/mL | - |
- Pediatric Studies: In trials involving children aged 2 years and older, raltegravir demonstrated a virologic success rate of approximately 53% at week 24 among treatment-experienced subjects. This indicates its efficacy across different age groups and treatment histories .
Safety Profile
Raltegravir is generally well-tolerated with a low incidence of severe adverse effects. Common side effects include nausea, headache, and fatigue. Importantly, it has a low potential for drug-drug interactions due to its unique metabolic pathway that does not involve cytochrome P450 enzymes .
Toxicity Studies:
Propiedades
IUPAC Name |
potassium;4-[(4-fluorophenyl)methylcarbamoyl]-1-methyl-2-[2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propan-2-yl]-6-oxopyrimidin-5-olate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C20H21FN6O5.K/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11;/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30);/q;+1/p-1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
IFUKBHBISRAZTF-UHFFFAOYSA-M |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=NN=C(O1)C(=O)NC(C)(C)C2=NC(=C(C(=O)N2C)[O-])C(=O)NCC3=CC=C(C=C3)F.[K+] |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C20H20FKN6O5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID501007339 |
Source
|
| Record name | Potassium 4-[{[(4-fluorophenyl)methyl]imino}(hydroxy)methyl]-1-methyl-2-{2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propan-2-yl}-6-oxo-1,6-dihydropyrimidin-5-olate | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501007339 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
482.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
871038-72-1 |
Source
|
| Record name | Raltegravir potassium [USAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0871038721 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Potassium 4-[{[(4-fluorophenyl)methyl]imino}(hydroxy)methyl]-1-methyl-2-{2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propan-2-yl}-6-oxo-1,6-dihydropyrimidin-5-olate | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501007339 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | potassium;4-[(4-fluorophenyl)methylcarbamoyl]-1-methyl-2-[2-[(5 methyl-1,3,4oxadiazole-2-carbonyl)amino]propan-2-yl]-6 oxopyrimidin-5-olate | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | RALTEGRAVIR POTASSIUM | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/43Y000U234 | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
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Retrosynthesis Analysis
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Feasible Synthetic Routes
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