Pharmacokinetic Effects of Coadministration of Lersivirine with Raltegravir or Maraviroc in Healthy Subjects

Vourvahis, Manoli; Langdon, Grant; LaBadie, Robert R.; Layton, Gary; Ndongo, Marie-Noella; Banerjee, Subhashis; Davis, John D.

doi:10.1128/aac.00572-11

Cited by 6 publications

(5 citation statements)

References 14 publications

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“…15 Lersivirine is a weak CYP3A4 inducer, although its further development was stopped in 2013. 102 In healthy subjects given 300 mg MVC and 500 mg Lersivirine twice daily, MVC Cmax and AUC increased by 3.4% and 6.2%, respectively, compared to subjects given MVC plus placebo. 102 NVP increased MVC Cmax and AUC by 101% and 154%, respectively 99 ( Table 2 ).…”

Section: Mvc Drug–drug Interactionsmentioning

confidence: 96%

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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Section: Mvc Drug–drug Interactionsmentioning

confidence: 96%

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

Woollard¹,

Kanmogne²

2015

DDDT

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“…No significant changes in lersivirine’s pharmacokinetic parameters were seen. The authors concluded that lersivirine and raltegravir could likely be co-administered without need for dose adjustments [25]. Additionally, the NNRTI rilprivirine was studied and also found to have little effect on the concentrations of raltegravir when used in combination [26].…”

Section: Raltegravirmentioning

confidence: 99%

“…A once daily fixed dose Quad regimen containing elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/ tenofovir 300 mg is currently in Phase 3 trials [25]. The Quad formulation has recently demonstrated 48 week non-inferiority in treatment naïve HIV-infected patients to atazanavir/ritonavir plus emtricitabine/tenofovir (90% vs. 87%, respectively) and to efavirenz/emtricitabine/tenofovir (88% vs. 84%, respectively ) in maintenance of viral RNA ≤ 50 copies/mL [57,58].…”

Section: Elvitegravirmentioning

confidence: 99%

Pharmacology of HIV integrase inhibitors

Adams

Greener

Kashuba

2012

Current Opinion in HIV and AIDS

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Purpose of Review The purpose of this paper is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir and elvitegravir (both in Phase III drug development). Recent Findings Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter- and intra-patient pharmacokinetic variability is high. Twice daily 400mg dosing has been shown to be clinically superior to 800mg once daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was FDA approved in December 2011. Cobicistat-boosted elvitegravir, and the second generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, while boosted elvitegravir participates in additional CYP3A mediated interactions. Summary Raltegravir’s potent antiretroviral activity has resulted in widespread use in both treatment naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.

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“…Most studies investigated compounds acting on the innate immune system (19 studies) ( 20 – 38 ), followed by compounds with immunoregulatory activity, classified into immunomodulatory (cereblon [CRBN] modulators; 14 studies) ( 39 – 44 , 46 – 52 ) and mediators of immune cell functions (CCR5 antagonists; 14 studies) ( 54 – 59 , 61 – 63 , 65 – 67 , 76 ). All the other compounds were investigated in only one or two HV studies.…”

Section: Resultsmentioning

confidence: 99%

Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds

Radanovic

Klarenbeek²,

Rißmann³

et al. 2022

Front. Oncol.

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AimTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology.MethodsLiterature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. “Immunotherapeutic” was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety.ResultsIn total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays.DiscussionHealthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, identifier CRD42020210861

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Pharmacokinetic Effects of Coadministration of Lersivirine with Raltegravir or Maraviroc in Healthy Subjects

Cited by 6 publications

References 14 publications

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

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

Pharmacology of HIV integrase inhibitors

Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds

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