Choose Your Country or Region

RALTEGRAVIR: A POTENT INTEGRASE INHIBITOR

by Selleckchem | Apr 01 2012

INTRODUCTION TO HIV-1 AND ITS TREATMENT:
HIV-1 is amongst the most destructive viruses and its treatment regime always in a need of more and novel methods to treat this virus because any of the new drugs gives a short time benefit as the virus get resistant against that drug, therefore any of the effective and newly introduced drug is welcomed by the medical practitioners. In order to integrate the genome of virus it needs integrase enzyme, thus inhibitors to this enzyme are potential candidates to inhibit the viral replication inside host cells. For the development and discovery of these inhibitors a lot of work is being done for integrase inhibitors of HIV-1 [1] these inhibitors are also offering new hopes for HIV-1 drugs [2]. Raltegravir integrase inhibitor, first FDA approved HIV integrase inhibitor [3] and the discovery of this inhibitor [4] was much valued.

RALTEGRAVIR:
Raltegravir is manufactured currently by Merck and it is available in the Raltegravir potassium salt form and the marketing name of this inhibitor is Isentress. Raltegravir is soluble in good number of solvents like DMSO, ethanol, methanol and also in water, this property make it useable by oral administration. A 1 mg vial of Raltegravir is a worth of $200 therefore Raltegravir price is very high. If someone wants to purchase Raltegravir one can buy it from any of the v Raltegravir supplier. One can only order Raltegravir for research and medicinal purposes. The structure of Raltegravir is based on the oxidazole ring.
The rationale of using Raltegravir was based on its efficacy and potent active action [5] these properties soon lead to the HIV patients’ treatment against its drug resistive nature [6]. Techniques like HPLC are used for the detection of metabolic analysis in the plasma [7] [8]. The metabolic pathway of Raltegravir inside the body is very promising along with disposition, thus leading this drug over other therapeutic [9]. In addition to the treatment of HIV-1 drug resistant and infection [10], Raltegravir has also been proved potent against Herpes virus. As discussed earlier Raltegravir mechanism behind the treatment of HIV is the targeting of integrase enzyme which ultimately leads to the inhibition of HIV-1 genome integration in human DNA. Raltegravir is found to be more potent than other present drugs [11] in addition to this it is also used in combination with Tenofovir which enhances the effect of treatment [12].

CLINICAL TRIALS OF RALTEGRAVIR:
As Raltegravir has potent actions against HIV-1 infection in case of both treated resistant patients and antiretroviral treatment, therefore the studies for the assessment of Raltegravir safety, efficacy, pharmacokinetics and tolerate ability was needed [13]. During clinical phase II trials Raltegravir was found as an effective inhibitor of 2nd stage of viral replication [14], these findings proved Raltegravir potential for treatment of HIV when used in a proper dose. The interaction profile of Raltegravir with other inhibitors was minimum so eliminates the need of altering dose for either inhibitors [15] hence making it an ideal for the combination therapy as well. This property was further confirmed by the clinical studies which generated remarkable results as Raltegravir effect was studied for 48 weeks during clinical trials[16] and in addition to these phase II study of Darunavir or Etravirine combination with Raltegravir [17]. Not only in combination but also alone therapy of Raltegravir was proved efficient during phase I and III of clinical trials [18] and in treatment regime it is found as much better than other inhibitors [19]. The resistance profile of Raltegravir [20] was taken from MDR virus trials during phase II [21] as this study used for the modification of dose kinetics accordingly.

REFERENCES:
1. Savarino, A., A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs, 2006.
2. Serrao, E.e.a., Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology, 2009.
3. Cocohoba, J.a.D., B.J., Raltegravir: The first HIV integrase inhibitor. Clinical Therapeutics, 2008.
4. Summa, V., Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection. J. Med. Chem., 2008.
5. Anker, M.a.C., R.B., Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opinion on Investigational Drugs, 2008.
6. Croxtall, J.D.a.K., S.J., Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. Drugs, 2009.
7. Heine, R.e.a., Quantification of the HIV-integrase inhibitor raltegravir and detection of its main metabolite in human plasma, dried blood spots and peripheral blood mononuclear cell lysate by means of high-performance liquid chromatography tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 2009.
8. Poirier, J.M.e.a., Quantification of the HIV-integrase inhibitor raltegravir (MK-0518) in human plasma by high-performance liquid chromatography with fluorescence detection. Journal of Chromatography B, 2008.
9. Kassahun, K.e.a., Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the HIV-1 Integrase Enzyme. Drug Metabolism and Disposition, 2007.
10. Steigbigel, R.T.e.a., Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med, 2008.
11. Marinello, J.e.a., Comparison of Raltegravir and Elvitegravir on HIV-1 Integrase Catalytic Reactions and on a Series of Drug-Resistant Integrase Mutants. Biochemistry, 2008.
12. Moss, D.M.e.a., Interaction between Raltegravir and Tenofovir. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011.
13. Markowitz, M.e.a., Antiretroviral Activity, Pharmacokinetics, and Tolerability of MK-0518, a Novel Inhibitor of HIV-1 Integrase, Dosed As Monotherapy for 10 Days in Treatment-Naive HIV-1-Infected Individuals. Journal of Acquired Immune Deficiency Syndromes, 2006.
14. Murray, J.M.e.a., Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS, 2007.
15. Anderson, M.S.e.a., Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects. Antimicrobial Agents and Chemotherapy, 2008.
16. Markowitz, M.e.a., Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr., 2007.
17. Yazdanpanah, Y.e.a., High Rate of Virologic Suppression with Raltegravir Plus Etravirine and Darunavir/Ritonavir among Treatment-Experienced Patients Infected with Multidrug-Resistant HIV: Results of the ANRS. Clin Infect Dis., 2009.
18. Steigbigel, R.T.e.a., Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials. Clin Infect Dis., 2010.
19. Lennox, J.L.e.a., Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. The Lancet, 2009.
20. Cooper, D.A.e.a., Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection. N Engl J Med, 2008.
21. Grinsztejn, B.e.a., Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. The Lancet, 2007.