Safety, Tolerability, and Pharmacokinetics of Raltegravir After Single and Multiple Doses in Healthy Subjects

Department of Clinical Pharmacology, Merck Research Laboratories, a division of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 03/2008; 83(2):293-9. DOI: 10.1038/sj.clpt.6100281
Source: PubMed


Raltegravir is a novel human immunodeficiency virus-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration (IC95)=33 nM in 50% human serum). Three double-blind, randomized, placebo-controlled, pharmacokinetic, safety, and tolerability studies were conducted: (1) single-dose escalation study (10-1,600 mg), (2) multiple-dose escalation study (100-800 mg q12 h x 10 days), and (3) single-dose female study (400 mg). Raltegravir was rapidly absorbed with a terminal half-life (t1/2) approximately 7-12 h. Approximately 7-14% of raltegravir was excreted unchanged in urine. Area under the curve (AUC)(0-infinity) was similar between male and female subjects. After multiple-dose administration, steady state was achieved within 2 days; there was little to modest accumulation of raltegravir. Trough levels were >33 nM for dose levels of 100 mg and greater. Raltegravir is generally well tolerated at doses of up to 1,600 mg/day given for up to 10 days and exhibits a pharmacokinetic profile supportive of twice-daily dosing with multiple doses of 100 mg and greater achieving trough levels >33 nM.

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    • "RAL is considered a first-generation INSTI based on its resistance profile. It exhibits potent activity against wild-type HIV-1, with an in vitro 95% inhibitory concentration of 15 ng/mL in 50% human serum.14 Resistance to RAL has been noted through one of three different pathways: Q148H/K/R ± G140S/A, N155H ± E92Q, and Y143C/R ± T97A. "
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    ABSTRACT: Raltegravir is an integrase strand-transfer inhibitor approved for the treatment of HIV infection. It was the first medication in a novel class of antiretroviral agents to be approved for use in the United States in 2007. Raltegravir exhibits potent activity against wild-type HIV-1, but resistance development has been noted through three different pathways. It is metabolized primarily through uridine diphosphate glucuronosyltransferase 1A1 and has a single inactive glucuronide metabolite. Raltegravir is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes and exhibits low potential for drug-drug interactions; however, strong uridine diphosphate glucuronosyltransferase 1A1 inhibitors or inducers can alter the pharmacokinetics of raltegravir. It is well tolerated, and the most commonly reported adverse effects include headache, nausea, and diarrhea. Serious adverse effects with raltegravir are rare but include rhabdomyolysis and severe skin and hypersensitivity reactions. It has been approved for use in both treatment-naïve and treatment-experienced patients and is a preferred first-line agent in both United States and European HIV treatment guidelines. Although initial approval was granted on 48-week data, 5-year clinical data have recently been published. This article reviews the data supporting long-term efficacy and safety of raltegravir in the treatment of HIV infection.
    Infection and Drug Resistance 03/2014; 7:73-84. DOI:10.2147/IDR.S40168
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    • "It is neither an inducer nor an inhibitor of P450 system, but it is substrate and inhibitor of P-glycoprotein and MRP1 [5,6]. Raltegravir is metabolized via UGT1A1-mediated glucuronidation and is neither an inducer nor an inhibitor of the CYP oxidation system or P-glycoprotein [7]. Maraviroc is extensively metabolized by CYP3A4 and it is a substrate for P-glycoprotein. "
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    ABSTRACT: The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.
    Malaria Journal 05/2011; 10(1):141. DOI:10.1186/1475-2875-10-141 · 3.11 Impact Factor
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    • "Oral absorption of raltegravir is rapid with a median time to maximum concentration of 0.5–1.3 hours, and oral bioavailability is approximately 30%.16 Plasma protein binding reaches 83%. "
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    ABSTRACT: Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class. At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naïve patients when associated with tenofovir and emtricitabine. Raltegravir was also found to be highly active in antiretroviral-experienced patients with virological failure and displaying multiresistant virus, as shown with the BENCHMRK and ANRS 139 TRIO trials. Finally, the use of raltegravir was assessed in the context of a switch strategy in antiretroviral-experienced patients with virological success [human immunodeficiency virus type 1 (HIV-1) RNA below detection limit], highlighting the following mandatory criteria in this strategy: the nucleoside reverse transcriptase inhibitors associated with raltegravir have to be fully active. In the different studies, raltegravir had a favorable safety and tolerability profile. In the clinical situation a switch in virologically suppressed patients receiving a protease inhibitor, an improvement of the lipid profile was observed. Overall, when analyzing the Phase II and III trials together, only a few patients on raltegravir discontinued for adverse events. The development of resistance to raltegravir mainly involved three resistance mutations in integrase gene: Q148H/K/R, N155H, and Y143C/H/R. In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naïve and in antiretroviral-experienced patients.
    Infection and Drug Resistance 10/2010; 3:103-14. DOI:10.2147/IDR.S8673
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