Raltegravir: the First HIV Integrase Inhibitor

Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco, California 94143, USA.
Clinical Therapeutics (Impact Factor: 2.73). 10/2008; 30(10):1747-65. DOI: 10.1016/j.clinthera.2008.10.012
Source: PubMed


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.

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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 [6]. Further, the pharmacokinetics of RAL showed important inter-or intra-subject variability [7]. "
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    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.
    Journal of Pharmaceutical Analysis 10/2014; 5(2). DOI:10.1016/j.jpha.2014.10.002
    • "Mirochnick and Capparelli (2004) extensively reviewed pharmacokinetics of antiretrovirals during pregnancy and concluded that the physiological changes associated with pregnancy alter the drug disposition and the need for dose optimization/adjustment in pregnant population directly depends on the magnitude of pharmacokinetic changes observed during pregnancy. Raltegravir, the first approved agent in the class of integrase inhibitors (Cocohoba and Dong, 2008), is a promising addition to the existing antiretroviral drugs. In the last decade clinicians have increasingly utilized raltegravir, along with other antiretroviral drugs, as the first line therapy to prevent motherto-child HIV transmission in pregnant women. "
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    ABSTRACT: Alterations in antiretroviral pharmacokinetics during pregnancy must be understood for the drugs to be used safely and effectively. Present study is an attempt to understand the potential changes in raltegravir plasma and cerebrospinal fluid pharmacokinetics during pregnancy in late pregnant and non-pregnant rats. In vitro plasma protein binding, metabolic stability, intravenous blood-brain barrier (BBB) permeability and oral pharmacokinetic studies were performed. Raltegravir concentrations in different matrices were measured using LC-MS/MS. Raltegravir plasma protein binding remained similar in both groups, whereas, metabolic stability was significantly lower in pregnant rats than the non-pregnant rats liver microsomes. In oral pharmacokinetic study, peak plasma concentrations and systemic exposures were significantly lower (∼37%) and clearance was significantly higher (∼61%) in late pregnant rats compared to non-pregnant rats. However, unlike plasma pharmacokinetics, CSF pharmacokinetic profile of raltegravir was similar in both pregnant and non-pregnant rats. Following intravenous administration, raltegravir showed higher BBB permeability in pregnant rats compared to non-pregnant rats. But the mean CSF-to-plasma ratio was significantly higher in pregnant rats compared to non-pregnant rats suggesting higher brain penetration in pregnant rats. In conclusion, pregnancy significantly affected the plasma pharmacokinetics, whereas cerebrospinal fluid pharmacokinetics remained fairly similar in pregnant and non-pregnant rats. Although current plasma pharmacokinetic data is in contradiction to the reported human data, pregnancy-specific pharmacokinetic changes observed in the current study emphasize the need for close therapeutic monitoring while treating the pregnant population and also warrants the need for the additional clinical data with larger group of patients.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 09/2014; 65. DOI:10.1016/j.ejps.2014.08.012 · 3.35 Impact Factor
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    • "Recently, raltegravir in combination treatment was listed as one of the preferred regimens recommended for treatment-naive HIV-1-infected patients. Clinical studies have shown that raltegravir was well-tolerated and had fewer side effects compared to other classes of antiretroviral drugs, such as HIV PIs and reverse transcriptase inhibitors [12]–[14]. Our recent study demonstrated that raltegravir is able to prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting the ER stress response [15]. "
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    ABSTRACT: HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages. In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages. Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART.
    PLoS ONE 03/2014; 9(3):e90856. DOI:10.1371/journal.pone.0090856 · 3.23 Impact Factor
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