Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment

Lefebvre, E.; Gottwald, Mildred D.; Lasseter, Kenneth C.; Chang, Wei‐An; Willett, Michael S.; Smith, Patrick F.; Somasunderam, Anoma; Utay, Netanya S.

doi:10.1111/cts.12397

Cited by 46 publications

(47 citation statements)

References 35 publications

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“…1C). Treatment of endothelial monolayer : Confluent HAoECs were treated for 4 h at 37°C with vehicle or antagonist (BMS‐22, MVC or CVC; 1 μM, a concentration similar to pharmacokinetic data reported in CVC‐treated patients) . Unbound inhibitor was removed by carefully washing the endothelium with ECGM MV2 before 0.2 × 10 6 live monocytes, as assessed by trypan blue exclusion, were added to the upper compartment on top of the HAoEC monolayer in a 1:1 mixture of ECGM MV:AIM‐V media (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

D’Antoni

Mitchell

McCurdy

et al. 2018

Journal of Leukocyte Biology

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Incidences of cardiovascular diseases (CVD) are high among virologically suppressed HIV-infected individuals. Monocyte activation and trafficking are key mechanisms in the evolution of CVD. We studied the ability of cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and CCR5 antagonist, to influence the migration of monocytes from HIV-infected individuals on antiretroviral therapy (ART). Monocytes were derived from 23 ART-suppressed HIV-infected and 16 HIV-uninfected donors. In a trans-endothelial migration model, monocytes, and human aortic endothelial cells (HAoECs) were exposed to cenicriviroc and migrated monocytes, quantified. Expression of CCR2 and CCR5 on monocytes and adhesion molecules (E-selectin, ICAM-1, VCAM-1, PECAM-1, and CD99) on HAoECs were measured. The single antagonists, BMS-22 (CCR2), and maraviroc (CCR5), served as controls. When both HAoECs and monocytes together were exposed to the antagonists, cenicriviroc led to a greater decrease in monocyte migration compared to BMS-22 or vehicle in both HIV-infected and HIV-uninfected groups (P < 0.05), with maraviroc having no inhibitory effect. Cenicriviroc treatment of HAoECs alone decreased monocyte migration in the HIV-infected group when compared to vehicle (P < 0.01). Inhibition of migration was not evident when monocytes alone were exposed to cenicriviroc, BMS-22 or maraviroc. Incubation of HAoECs with cenicriviroc decreased E-selectin expression (P = 0.045) but had limited effects on the other adhesion molecules. Cenicriviroc inhibits monocyte trans-endothelial migration more effectively than single chemokine receptor blockade, which may be mediated via disruption of monocyte-endothelial tethering through reduced E-selectin expression. Cenicriviroc should be considered as a therapeutic intervention to reduce detrimental monocyte trafficking.

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Section: Methodsmentioning

confidence: 99%

Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

D’Antoni

Mitchell

McCurdy

et al. 2018

Journal of Leukocyte Biology

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“…Cenicriviroc (CVC), a CCR2/CCR5 antagonist, is currently being evaluated for the treatment of NASH and liver fibrosis (CENTAUR, NCT02217475, Table 1). Cenicriviroc showed favorable safety profile in HIV-infected patients in a phase 2b study [93] and in patients with hepatic impairment [94]. …”

Section: Developments In Targeted Therapy Related To Liver Fibrosismentioning

confidence: 99%

Clinical Advancements in the Targeted Therapies against Liver Fibrosis

Bansal

Nagórniewicz

Prakash

2016

Mediators of Inflammation

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Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.

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“…Vitamin E therapy, compared with placebo, was associated with a significantly higher rate of improvement in NASH (43% vs. 19%) Cenicriviroc (CVC), a dual‐CCR2/CCR5 antagonist, showed potent anti‐inflammatory and anti‐fibrotic activity in animal models, and its safety and pharmacokinetic results were recently published . This therapy is currently being tested in patients with NASH. Several additional compounds that have been tested in NASH have direct and indirect anti‐inflammatory properties, that is, fatty acid–bile acid conjugates that serve as metabolic modulators, anti‐lysyl‐oxidase 2 monoclonal antibody, which has anti‐fibrotic effects, vitamin D, an immunomodulatory molecule and renin–angiotensin–aldosterone system blockers …”

Section: The Immune System As a Target For The Treatment Of Nashmentioning

confidence: 99%

Review article: novel methods for the treatment of non-alcoholic steatohepatitis - targeting the gut immune system to decrease the systemic inflammatory response without immune suppression

Ilan

2016

Aliment Pharmacol Ther

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SummaryBackgroundThe systemic immune system plays a role in inflammation and fibrogenesis associated with non‐alcoholic steatohepatitis (NASH) and has become a potential target for drug development. In particular, the gut immune system has been suggested as a means for generating signals that can target the systemic immune system.AimTo describe seven novel methods being developed for the treatment of NASH that target the gut immune system for alleviation of the systemic inflammatory response, including oral administration of fatty‐liver‐derived proteins, anti‐CD3 antibodies, tumour necrosis factor fusion protein, anti‐lipopolysaccharide antibodies, glucosylceramide, delayed‐release mercaptopurine, and soy‐derived extracts.MethodsA search for these methods for oral immunotherapy for NASH was conducted.ResultsOral administration of these compounds provides an opportunity for immune modulation without immune suppression, with the advantage of being independent of a single molecular/inflammatory pathway. These modes of oral immune therapy demonstrate superior safety profiles, such that the patient is not exposed to general immune suppression. Moreover, these approaches target the whole spectrum of the disease and may serve as adjuvants to other therapies, such that they provide a platform for treatment of concomitant disorders in patients with NASH, including diabetes and hyperlipidaemia. Most of the compounds reviewed are currently in phase II trials, and it is anticipated that the acquisition of more clinical data in the next few years will enable the use of this new class of drugs for the treatment of NASH.ConclusionOral immunotherapy may provide a novel platform for the treatment of NASH.

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Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment

Cited by 46 publications

References 35 publications

Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

Clinical Advancements in the Targeted Therapies against Liver Fibrosis

Review article: novel methods for the treatment of non-alcoholic steatohepatitis - targeting the gut immune system to decrease the systemic inflammatory response without immune suppression

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