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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration = 33 nM in 50% human serum). In vitro characterization of raltegravir inhibition potential was assessed against a panel of cytochrome P450 (CYP) enzymes. An open-label, 2-period study was conducted to assess the effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP 3A4 probe substrate: period 1, 2.0 mg of midazolam; period 2, 400 mg of raltegravir every 12 hours for 14 days with 2.0 mg of midazolam on day 14. There was no meaningful in vitro effect of raltegravir on inhibition of a panel of CYP enzymes and induction of CYP 3A4. In the presence of raltegravir, midazolam area under the curve extrapolated to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)) geometric mean ratios were similar (geometric mean ratios and 90% confidence intervals: 0.92 [0.82, 1.03] (P = .208) and 1.03 [0.87, 1.22] (P = .751), respectively). No substantial differences were observed in T(max) (P = .750) or apparent half-life (P = .533) of midazolam. Plasma levels of midazolam were not substantially affected by raltegravir, which implies that raltegravir is not a clinically important inducer or inhibitor of CYP 3A4 and that raltegravir would not be expected to affect the pharmacokinetics of other drugs metabolized by CYP 3A4 to a clinically meaningful extent.
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PMID:Lack of a pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. 1807 30

* Raltegravir, the first in a new class of orally administered HIV type-1 (HIV-1) integrase inhibitors, selectively inhibits the strand transfer activity of HIV-1 and its integration into human DNA, a key stage in retroviral propagation, thereby limiting viral replication and the infection of new cells. * In two randomized, double-blind (with in-house blinding), placebo-controlled, multicentre, ongoing phase III trials, the proportion of patients achieving HIV-1 RNA loads of <400 copies/mL (primary endpoint) was significantly greater in raltegravir plus optimized background therapy (OBT) recipients than in placebo plus OBT recipients (preliminary 24-week results). * The proportion of patients achieving viral loads of <50 copies/mL was significantly greater with raltegravir plus OBT than with placebo plus OBT in the two studies. * In addition, mean CD4+ cell counts (secondary endpoint) were significantly increased from baseline in patients receiving raltegravir plus OBT relative to those receiving placebo plus OBT. * Raltegravir therapy was well tolerated overall. The incidence of mild to moderate adverse events was similar in the raltegravir and placebo arms of the two randomized trials.
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PMID:Raltegravir. 1808 77

Integrase is essential for HIV-1 replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. Raltegravir is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against wild-type and multi-class resistant HIV-1 virus (in vitro IC(95) for HIV-1 in 50% normal human serum = 33 nM). Inhibition of integrase prevents insertion of HIV DNA into the human DNA genome, thus blocking the ability of HIV to replicate. Raltegravir is administered orally every 12 h and does not require boosting with low-dose ritonavir (RTV) to achieve therapeutic concentrations. Raltegravir is not a potent inhibitor or inducer of cytochrome P450 3A4, and it is predominantly metabolized by glucuronidation, specifically by the enzyme UDP-glucuronosyltransferase 1A1.
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PMID:Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. 1809 22

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.
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PMID:Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. 1844 33

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.
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PMID:Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. 1851 46

Enfuvirtide has been a cornerstone of salvage therapy for multidrug-resistant HIV. Raltegravir provides another novel class option, with the advantages of easier administration and improved tolerability. Thirty-five adults electively replaced enfuvirtide with raltegravir while the rest of their regimen was unchanged. All maintained virologic suppression after a median of 7 months except one who experienced a transiently detectable viral load after 5 months. The new regimen was well tolerated with no apparent new drug-related adverse clinical or laboratory events.
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PMID:Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. 1852 70

HIV-1 integrase catalyzes the insertion of HIV-1 DNA into the genome of the host cell and, therefore, represents a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. Raltegravir, marketed as Isentress, is the first integrase inhibitor to be approved by the FDA for the treatment of HIV AIDS infection. This review briefly describes the successful medicinal chemistry efforts that culminated in the discovery of raltegravir, and highlights more recent progress that has been made in the field of HIV-1 integrase inhibition.
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PMID:Integrase inhibitors for the treatment of HIV infection. 1860 May 64

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC(0-12)) and peak plasma drug concentration (C(max)) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C(12)) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C(24), AUC, and C(max) GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.
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PMID:Lack of a significant drug interaction between raltegravir and tenofovir. 1862 63

Raltegravir (formerly known as MK-0518; Isentress) is the first in a new class of integrase inhibitors approved for the use in treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple antiretroviral agents. It is dosed twice daily with or without food. Raltegravir is a novel antiretroviral that has been shown to be well tolerated. It has demonstrated potent efficacy in the virologic suppression of HIV-1 RNA levels up to 48 weeks in two controlled studies that were conducted in clinically advanced, three-class antiretroviral, treatment-experienced adults.
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PMID:Raltegravir: the first in a new class of integrase inhibitors for the treatment of HIV. 1866 8

Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
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PMID:Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. 1876 51


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