Pharmacokinetics, Safety, and Tolerability of Maraviroc in HIV-Negative Subjects with Impaired Renal Function

Vourvahis, Manoli; Fang, Juanzhi; Checchio, Tina; Milton, Ashley; Weatherley, B.C.; McFadyen, Lynn; Heera, Jayvant

doi:10.1310/hct1403-99

Cited by 11 publications

(6 citation statements)

References 17 publications

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“…MVC concentration of 5 μM used in most of the experiments of this study resulted in no toxicity in vitro and was under the concentration required for mediating cell proliferation 28 . Furthermore, the transcriptomic profile of CD4+ T lymphocytes from MVC-treated patients remained unchanged, except for a non-significant tendency to reduction of TNF gene expression 64 , which was later confirmed through in vitro studies 65 . This suggests that cytokine release remains stable after MVC exposure.…”

Section: Discussionmentioning

confidence: 74%

The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1

López-Huertas

Jiménez-Tormo

Madrid-Elena

et al. 2017

Sci Rep

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A potential strategy to cure HIV-1 infection is to use latency reversing agents (LRAs) to eliminate latent reservoirs established in resting CD4+ T (rCD4+) cells. As no drug has been shown to be completely effective, finding new drugs and combinations are of increasing importance. We studied the effect of Maraviroc (MVC), a CCR5 antagonist that activates NF-κB, on HIV-1 replication from latency. HIV-1-latency models based on CCL19 or IL7 treatment, before HIV-1 infection were used. Latently infected primary rCD4+ or central memory T cells were stimulated with MVC alone or in combination with Bryostatin-1, a PKC agonist known to reverse HIV-1 latency. MVC 5 μM and 0.31 μM were chosen for further studies although other concentrations of MVC also increased HIV-1 replication. MVC was as efficient as Bryostatin-1 in reactivating X4 and R5-tropic HIV-1. However, the combination of MVC and Bryostatin-1 was antagonistic, probably because Bryostatin-1 reduced CCR5 expression levels. Although HIV-1 reactivation had the same tendency in both latency models, statistical significance was only achieved in IL7-treated cells. These data suggest that MVC should be regarded as a new LRA with potency similar as Bryostatin-1. Further studies are required to describe the synergistic effect of MVC with other LRAs.

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Section: Discussionmentioning

confidence: 74%

The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1

López-Huertas

Jiménez-Tormo

Madrid-Elena

et al. 2017

Sci Rep

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“…It is only used in treatment‐experienced individuals with R5 tropic virus, and requires a tropism test before initiation . Maraviroc is minimally cleared by the kidneys and by dialysis, and does not need to be dose‐reduced in ESRD . However, because high levels were observed in patients with mild to moderately reduced kidney function (CrCl 30‐80 mL/min) when coadministered with certain PIs, it is recommended to avoid concomitant use of CYP34A inducers or inhibitors with maraviroc in this setting .…”

Section: Antiretroviral Therapymentioning

confidence: 99%

HIV in the dialysis population: Current issues and future directions

Boyle

Lee

Wyatt

2017

Seminars in Dialysis

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Antiretroviral therapy has significantly reduced mortality due to HIV infection, but the aging HIV-positive patient population now faces a growing burden of comorbidity. This review describes the changing epidemiology of chronic kidney disease and end-stage renal disease in this population, and highlights recent advances in antiretroviral therapy and kidney transplantation that directly impact the care of patients with HIV infection and end-stage renal disease.

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“… 63 In individuals with severe renal impairment, MVC renal clearance was fourfold lower than in patients with normal renal function (27 versus 110 mg/min, respectively). 64 In a patient with end-stage liver disease and renal impairment receiving 300 mg/kg MVC, raltegravir (RAL), and enfuvirtide (ENF) twice daily, MVC serum concentrations were 25-fold higher than expected, and remained high after doses were adjusted to every 48 hours. 65 No dose adjustment is necessary in patients with mild-to-moderate renal impairment, but in patients with severe renal impairment or end-stage renal disease, MVC should not be given if the patient is also taking CYP3A4 inducers or inhibitors.…”

Section: Mvc Pharmacodynamicsmentioning

confidence: 99%

Maraviroc: a review of its use in HIV infection and beyond

Woollard¹,

Kanmogne²

2015

DDDT

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The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug–drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.

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Pharmacokinetics, Safety, and Tolerability of Maraviroc in HIV-Negative Subjects with Impaired Renal Function

Cited by 11 publications

References 17 publications

The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1

The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1

HIV in the dialysis population: Current issues and future directions

Maraviroc: a review of its use in HIV infection and beyond

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