Raltegravir: The First HIV Integrase Inhibitor
ABSTRACT The availability of new classes of antiretroviral drugs has made it possible for HIV-infected individuals who are highly treatment experienced to achieve the goals of immunologic recovery and virologic suppression. Raltegravir is the first integrase inhibitor to be approved by the US Food and Drug Administration for use in antiretroviral treatment- experienced adult patients with viral resistance.
This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, tolerability, resistance profile, drug interactions, and dosing and administration of raltegravir.
Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to July 2008 were conducted using the terms integrase, raltegravir, and MK-0518. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (1998-2008); Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2007); International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (2001-2007); and European AIDS Conference (2001-2007) were also searched.
Raltegravir blocks HIV replication by inhibiting essential strand-transfer activities of integrase. Raltegravir is rapidly absorbed, with a median T(max) of approximately 4 hours in the fasting state. No dose adjustment is recommended in patients with moderate renal or hepatic insufficiency, and raltegravir may be taken without regard to meals. In Phase II studies in treatment-naive patients, raltegravir had efficacy similar to that of standard initial therapies. In 2 interrelated Phase III clinical studies in treatment-experienced patients with drug-resistant disease, the addition of raltegravir to an optimized background regimen significantly lowered HIV RNA compared with optimized background treatment alone (62.1% vs 32.9%, respectively; P < 0.001). Raltegravir was generally well tolerated. The most common adverse effects reported in Phase II/III trials in treatment-experienced patients were diarrhea (16.6%), nausea (9.9%), and headache (9.7%). Cytochrome P450-related drug interactions are not expected, as raltegravir is not a CYP substrate, inducer, or inhibitor. However, to prevent failure of raltegravir, the drug should not be coadministered with rifampin.
Raltegravir is a potent and generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretrovirals.
- SourceAvailable from: Mallika Sanyal
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- "It undergoes hepatic metabolism mainly by uridine diphosphate glucuronosyltranferase enzyme to give an inactive glucuronide metabolite, with only 9 % of the administered dose excreted unchanged in the urine . Further, the pharmacokinetics of RAL showed important inter-or intra-subject variability . "
ABSTRACT: A selective and rapid high performance liquid chromatography-tandem mass spectrometry method has been developed and validated for the quantification of raltegravir using raltegravir-d3 as an internal standard (IS). The analyte and IS were extracted with methylene chloride and n-hexane solvent mixture from 100 µL human plasma. The chromatographic separation was achieved on a Chromolith RP-18e endcapped C18 (100 mm × 4.6 mm) column in a run time of 2.0 min. Quantitation was performed in the negative ionization mode using the transitions of m/z 443.1→316.1 for raltegravir and m/z 446.1 →319.0 for IS. The linearity of the method was established in the concentration range of 2.0–6000 ng/mL. The mean extraction recovery for raltegravir and IS was 92.6% and 91.8% respectively and the IS-normalized matrix factors for raltegravir ranged from 0.992 to 0.999. The application of this method was demonstrated by a bioequivalence study with 18 healthy subjects.10/2014; 5(2). DOI:10.1016/j.jpha.2014.10.002
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- "Other drugs act as HIV-1 protease (HIV-1PR) inhibitors, for example, Amprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir , and Saquinavir       . More recently, integrase inhibitors have been developed, including Raltegravir   . The current treatments have encountered drug resistance problems from virus mutations and, in addition, can cause serious side effects. "
ABSTRACT: We applied molecular dynamics simulations to investigate the binding properties of a designed ankyrin repeat protein, the DARPin-CD4 complex. DARPin 23.2 has been reported to disturb the human immunodeficiency virus (HIV) viral entry process by Schweizer et al. The protein docking simulation was analysed by comparing the specific ankyrin binder (DARPin 23.2) to an irrelevant control (2JAB) in forming a composite with CD4. To determine the binding free energy of both ankyrins, the MM/PBSA and MM/GBSA protocols were used. The free energy decomposition of both complexes were analysed to explore the role of certain amino acid residues in complex configuration. Interestingly, the molecular docking analysis of DARPin 23.2 revealed a similar CD4 interaction regarding the gp120 theoretical anchoring motif. In contrast, the binding of control ankyrin to CD4 occurred at a different location. This observation suggests that there is an advantage to the molecular modification of DARPin 23.2, an enhanced affinity for CD4.Journal of molecular graphics & modelling 09/2011; 31:65-75. DOI:10.1016/j.jmgm.2011.09.003 · 2.02 Impact Factor
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- "INIs target the key enzyme integrase of HIV-1, essential for viral replication, and thus they are some of the most promising anti HIV-1 compounds (Ceccherini-Silberstein et al., 2009; McNeely et al., 2008; Schafer and Squires, 2009). For instance, one of the most exciting recent advances in HIV-1 pharmacotherapy has been the approval in the October 2007 by Food and Drug Administration (FDA) of the first INI, the new pyrimidone carboxamide raltegravir (RAL) provided with a high potency and generally well tolerability (Cocohoba and Dong, 2008; Goffinet et al., 2009; Moltò et al., 2011; Steigbigel et al., 2008; Summa et al., 2008). "
ABSTRACT: The activity of raltegravir and 4 other integrase inhibitors (MK-2048, L870,810, IN2, and IN5) was investigated in primary human macrophages, PBMC and C8166-lymphocytic T cells, in order to determine their relative potency and efficacy in different cellular systems of HIV infection. Raltegravir showed better protective efficacy in all cell types; MK-2048, L870,810 and IN5 showed a potent anti-HIV-1 activity in macrophages, while in lymphocytes only MK-2048 and L870,810 showed an inhibitory effect comparable to raltegravir. IN2 was a poorly effective anti-HIV-1 compound in all cellular systems. All effective integrase inhibitors exhibited a potent antiviral activity against both X4 and R5 HIV-1 strains. In general, raltegravir, MK-2048, L870,810 and IN5 showed anti HIV activity similar or slightly higher in macrophages compared to PBMC and C8166 T cells: for MK-2048, the EC(50) was 0.4, 0.9, 11.5 nM in macrophages, in PBMCs and T cells, respectively; for L870,810, the EC(50) was 1.5, 14.3, and 10.6 nM, respectively; for IN5 the EC(50) was 0.5, 13.7, and 5.7 nM, respectively.Antiviral research 08/2011; 92(2):255-61. DOI:10.1016/j.antiviral.2011.08.008 · 3.94 Impact Factor