Cobicistat: Review of a Pharmacokinetic Enhancer for HIV Infection

Sherman, Elizabeth M; Worley, Marylee V.; Unger, Nathan R.; Gauthier, Timothy P.; Schafer, Jason J.

doi:10.1016/j.clinthera.2015.07.022

Cited by 43 publications

(28 citation statements)

References 25 publications

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“…33 The compounds were orally fed to mice for a period of eight consecutive days followed by analysis of bone marrow cells (Figure 8a). Cells were analysed via FACS using specific cell surface markers, CD45 and CD25, to understand the effect of Elvitegravir on B-cell development in vivo, after gating the total lymphocyte population.…”

Section: Resultsmentioning

confidence: 99%

HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

et al. 2017

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Integrase inhibitors are a class of antiretroviral drugs used for the treatment of AIDS that target HIV integrase, an enzyme responsible for integration of viral cDNA into host genome. RAG1, a critical enzyme involved in V(D)J recombination exhibits structural similarity to HIV integrase. We find that two integrase inhibitors, Raltegravir and Elvitegravir, interfered with the physiological functions of RAGs such as binding, cleavage and hairpin formation at the recombination signal sequence (RSS), though the effect of Raltegravir was limited. Circular dichroism studies demonstrated a distinct change in the secondary structure of RAG1 central domain (RAG1 shares DDE motif amino acids with integrases), and when incubated with Elvitegravir, an equilibrium dissociation constant (Kd) of 32.53±2.9 μM was determined by Biolayer interferometry, leading to inhibition of its binding to DNA. Besides, using extrachromosomal assays, we show that Elvitegravir inhibited both coding and signal joint formation in pre-B cells. Importantly, treatment with Elvitegravir resulted in significant reduction of mature B lymphocytes in 70% of mice studied. Thus, our study suggests a potential risk associated with the use of Elvitegravir as an antiretroviral drug, considering the evolutionary and structural similarities between HIV integrase and RAGs.

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Section: Resultsmentioning

confidence: 99%

HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

et al. 2017

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“…Inhibition of intestinal (and hepatic) CYP3A enzymes may therefore shorten the time interval to reach therapeutic serum levels of mitotane (44). There are already inhibitors of CYP3A4 used in the clinic like ritonavir or cobicistat, which are pharmacokinetic enhancers of protease inhibitors (45,46). Our observation is limited by the availability of only one suitable case.…”

Section: Discussionmentioning

confidence: 98%

Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma

Kroiß

Plonné²,

Kendl

et al. 2016

European Journal of Endocrinology

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“…With the introduction of TAF, the coformulated tablet elvitegravir/cobicistat/TAF/emtricitabine can be used in those with creatinine clearance of 30-69 ml/min (38). There is no experience with this drug at lower levels of kidney function, and drug-drug interactions have not been evaluated (61).…”

Section: Pharmacoenhancers Cobicistatmentioning

confidence: 99%

Clinical Pharmacology in HIV Therapy

Atta

Seigneux

Lucas

2018

CJASN

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The success of combination antiretroviral therapy in the treatment of HIV-1-positive individuals has shifted clinical attention toward combination antiretroviral drug regimens that optimize tolerability, long-term safety, and durable efficacy. Wherever patients have access to treatment, morbidity and mortality are increasingly driven by non-HIV-associated comorbidities, which may be observed earlier than in age-matched controls and despite the best available combination antiretroviral therapy. Similarly, HIV-1-positive individuals are now diagnosed and treated earlier with anticipated lifelong therapy. The contribution of specific antiretroviral agents to long-term morbidity and mortality is dependent on the pharmacologic characteristics of these agents, and it is increasingly important in this context.

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Cobicistat: Review of a Pharmacokinetic Enhancer for HIV Infection

Cited by 43 publications

References 25 publications

HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma

Clinical Pharmacology in HIV Therapy

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