Atazanavir Modestly Increases Plasma Levels of Raltegravir in Healthy Subjects

Iwamoto, Marian; Wenning, Larissa; Mistry, Goutam C.; Petry, Amelia S.; Liou, Sarah Y.; Ghosh, Kaylan; Breidinger, Sheila; Azrolan, Neal; Gutiérrez, María J.; Bridson, William E.; Stone, Julie A.; Gottesdiener, Keith; Wagner, John A.

doi:10.1086/588794

Cited by 83 publications

(89 citation statements)

References 7 publications

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“…This result is consistent with the studied preclinical and clinical interaction profile of raltegravir wherein raltegravir has been demonstrated to show only modest to insignificant effects on the pharmacokinetics of coadministered drugs (5,6,20; raltegravir prescribing information, Merck & Co., Inc.).…”

Section: Discussionsupporting

confidence: 86%

“…Etravirine has been shown to possess a relatively complex drug interaction profile with known inductive and inhibitory properties (7). In contrast, raltegravir is not an inducer or inhibitor of enzymes involved in drug metabolism, including those involved in etravirine metabolism (5,6,20; raltegravir prescribing information, Merck & Co., Inc.). Thus, the assessment of an effect of etravirine on the pharmacokinetics of raltegravir was supported by the drug interaction profile associated with etravirine.…”

Section: Discussionmentioning

confidence: 99%

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Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Anderson

Kakuda²,

Hanley

et al. 2008

Antimicrob Agents Chemother

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Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval ( No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Anderson

Kakuda²,

Hanley

et al. 2008

Antimicrob Agents Chemother

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“…Atazanavir is an inhibitor of UGT1A1 (42), and the coadministration of atazanavir (400 mg once a day [QD]) with raltegravir (100 mg single dose) resulted in increased raltegravir plasma area under the concentration-time curve (AUC), C max , and C min values of 72%, 53%, and 95%, respectively (20). This interaction was also confirmed in a separate study (43).…”

mentioning

confidence: 84%

Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir

Moss

Kwan

Liptrott

et al. 2011

Antimicrob Agents Chemother

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The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEM VBL100 , and Caco-2 cells. Transport by uptake transporters was assessed by using a Xenopus laevis oocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEM VBL100 , and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The K m and V max for SLC22A6 transport were 150 M and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentrationdependent manner. Raltegravir inhibited 1 M tenofovir with a 50% inhibitory concentration (IC 50 ) of 14.0 M, and tenofovir inhibited 1 M raltegravir with an IC 50 of 27.3 M. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.HIV infection and AIDS continue to be a major cause of worldwide mortality in the 21st century. A UNAIDS/WHO report in 2009 estimated that 33.4 million people worldwide were infected with HIV in 2008, with AIDS-related deaths numbering 2 million. Recent attempts to develop a vaccine for HIV have been largely unsuccessful (18). This, combined with increasing drug resistance, has emphasized the need to develop new drugs with unique mechanisms of action.Raltegravir represents a new class of antiretroviral treatment (8), targeting the HIV-1 integrase enzyme by binding to the active site and preventing viral DNA insertion into the host genome (11). Recent trials have shown raltegravir to have a sustained antiretroviral effect and good tolerability in treatment-experienced HIV-1 patients (33). The primary route of raltegravir metabolism is glucuronidation via UGT1A1, and raltegravir is not a substrate or an inhibitor of the major cytochrome P450 enzymes (19,24). However, the involvement of human drug transporters in raltegravir absorption, disposition, metabolism, and excretion (ADME) has not been fully investigated. Raltegravir has been described as being an ABCB1 substrate (25), but there are no data yet in the public domain. Raltegravir has shown higher concentrations (1.7-fold) in semen (4) and lower concentrations (0.04-to 0.39-fold) in cerebrospinal fl...

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“…Pharmacokinetic data obtained from healthy volunteers indicate a moderate increase in plasma levels of raltegravir administered with atazanavir alone or in combination with ritonavir. 43 Though coadministration with atazanavir resulted in increased plasma concentrations of raltegravir, no serious adverse effects or toxicities were reported in the study. Instead, this interaction could be favorable as it results in increased raltegravir trough concentrations.…”

Section: Drug Interactions With Antiretroviralsmentioning

confidence: 77%

Raltegravir: The evidence of its therapeutic value in HIV-1 infection

Ramkumar

Neamati

2009

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Atazanavir Modestly Increases Plasma Levels of Raltegravir in Healthy Subjects

Cited by 83 publications

References 7 publications

Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir

Raltegravir: The evidence of its therapeutic value in HIV-1 infection

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