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: 7.39). 03/2008; 83(2):293-9. DOI: 10.1038/sj.clpt.6100281
Source: PubMed

ABSTRACT 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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Available from: Steven Ramael, Jul 30, 2015
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    • "Clinical studies have shown that raltegravir was well tolerated and had fewer side effects compared with other classes of antiretrovirals, such as HIV PIs and reverse transcriptase inhibitors (Hughes et al., 2009). The peak plasma concentration ranges from 10.63 to 24.67 ␮M with 400-to 800-mg/day doses (Iwamoto et al., 2008c). "
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    ABSTRACT: Hyperlipidemia associated with the HIV protease inhibitor (PI), the major component of highly active antiretroviral treatment (HAART) for HIV infection, has stimulated interest in developing new agents that minimize these side effects in the clinic. HIV integrase inhibitor is a new class of anti-HIV agents. Raltegravir is a first-in-its-class oral integrase inhibitor and has potent inhibitory activity against HIV-1 strains that are resistant to other antiretroviral regimens. Our previous studies have demonstrated that HIV PI-induced endoplasmic reticulum (ER) stress links to dysregulation of lipid metabolism. However, little information is available as to whether raltegravir would have similar effects as the HIV PIs. In this study, we examined the effect of raltegravir on lipid metabolism both in primary rat hepatocytes and in in vivo mouse models, and we further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed development of dyslipidemia. The results indicated that raltegravir did not induce ER stress or disrupt lipid metabolism either in vitro or in vivo. However, HIV PI-induced ER stress and lipid accumulation were significantly inhibited by raltegravir both in in vitro primary rat hepatocytes and in in vivo mouse liver. High-performance liquid chromatography analysis further demonstrated that raltegravir did not affect the uptake and metabolism of HIV PIs in hepatocytes. Thus, raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of lipid metabolism by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the side effects associated with current HAART.
    Journal of Pharmacology and Experimental Therapeutics 08/2010; 334(2):530-9. DOI:10.1124/jpet.110.168484 · 3.86 Impact Factor
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    • "If only the current 400mg formulation of raltegravir can be used, pharmacokinetic data is already available for raltegravir at the 400mg once daily dose, in combination with atazanavir [18]. There are clinical trials underway evaluating the 800mg once daily dose, and the pharmacokinetics of raltegravir, with a long terminal elimination half-life, may support once daily dosing [19]. However the dose-ranging trials in this review only evaluated twice-daily dosing. "
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    ABSTRACT: Four million people have been initiated on antiretroviral treatment in low and middle income countries. However, an additional 5 million people eligible for treatment are not receiving it. Of the 27-29 million people infected with HIV but not currently receiving treatment, most will need to start antiretrovirals as their disease progresses. Funding for access programmes is restricted, partly because of the Global Financial Crisis. Antiretroviral treatment programmes have to lower overall costs, so that the maximum number of people with HIV can be treated for limited budgets. Antiretroviral treatment can account for the majority of the total cost of access programmes. During the development of antiretrovirals, several doses are normally evaluated in Phase 2 dose-ranging trials. In the case of efavirenz, lopinavir/ritonavir and raltegravir, there was no difference in efficacy between doses evaluated at Phase 2, but the higher doses were then taken into Phase 3 registration trials, leading to regulatory approval. Re-analysis of the dose-ranging trials of raltegravir showed equal efficacy for doses in the range of 100 to 600mg twice daily. The main Phase 2 trial of efavirenz, DMP-005, suggests that a 400mg once daily dose should show equal efficacy to the standard 600mg once daily dose. The dose-ranging trials of lopinavir/ritonavir showed the highest efficacy at the 200/100mg mg twice daily dose, compared with the standard 400/100 mg twice daily dose. Re-optimisation of doses could dramatically lower costs of first and second-line treatment for low and middle income countries. For example, it may be possible to manufacture raltegravir 100 mg twice daily for US $75-100, allowing first-line use in low income countries. Costs of efavirenz could be lowered by 30%, and lopinavir/ritonavir by 35%, using re-optimised doses. There may also be safety benefits to these new doses.
    The Open Infectious Diseases Journal 4(1). DOI:10.2174/1874279301004010085
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    ABSTRACT: The biggest challenge facing highly antiretroviral-experienced patients and their caregivers is the diminishing number of therapeutic options available that sustain activity despite increasing numbers of drug-resistance mutations. New options in antiretroviral treatment have been introduced: two new members of traditional antiretroviral classes (darunavir and etravirine) and two drugs with novel mechanisms of action (raltegravir and maraviroc). Each was approved for use in treatment-experienced patients. A fifth drug—containing efavirenz, tenofovir, and emtricitabine (Atripla; Bristol-Myers Squibb, New York, NY, and Gilead Sciences, Foster City, CA)—is a novel coformulation of existing drugs from two different classes, simplifying administration with the intent of increasing adherence. Because successful management of HIV infection requires the simultaneous use of three or more drugs, understanding the pharmacologic aspects of coadministration is critical. This review summarizes the pharmacokinetic properties affecting the administration of these recently approved drugs in light of highly active antiretroviral treatment guidelines.
    Current HIV/AIDS Reports 02/2009; 6(1):43-50. DOI:10.1007/s11904-009-0007-y
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