Effect of Vicriviroc on the QT/Corrected QT Interval and Central Nervous System in Healthy Subjects

Abstract

Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallelgroup study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.Vicriviroc maleate is a novel CCR5 antagonist that is currently in late-stage clinical development as part of a ritonavirboosted protease inhibitor regimen for HIV-1-infected individuals. In clinical studies, vicriviroc has demonstrated potent and durable virologic suppression, immunologic activity, and generally favorable tolerability (5).The current report describes two phase I studies that investigated the cardiac and central nervous system (CNS) safety, respectively, of vicriviroc in normal healthy adult volunteers. The first study was performed in accordance with the standard guidance for industry, which requires a comprehensive evaluation of cardiac safety for the safe conduct of drug development programs and drug registration, including those for vicriviroc (9). These assessments characterize the potential for new agents to prolong the QT/corrected QT (QTc) interval and to induce cardiac arrhythmias, such as torsade de pointes (TdP) and other ventricular tachyarrhythmias (1, 2, 8). Vicriviroc was studied both at a supratherapeutic dose and at the intended clinical dose in comparison with a placebo (negative control) and moxifloxacin (positive control). The effect of vicriviroc was evaluated in the presence of ritonavir, since the intended clinical administration of vicriviroc is to be part of an...

Existing highly accumulating lysosomotropic drugs with potential for repurposing to target COVID-19

“… Footnote: Data sources: phospholipidosis [ 26 , 31 ], accumulation in cells calculated according to [ 30 ], molecular and phys-chem properties from PubChem [ 44 ] and DrugBank [ 63 ] ( https://www.drugbank.ca/ ), hepatotoxicity from LiverTox [ 36 ], broad spectrum antiviral activity [ 23 ] ( https://drugvirus.info/ ), pharmacokinetics and cardiotoxicity ([ 46 , [48] , [49] , [50] , [51] , [52] , 54 , 55 , [57] , [58] , [59] , [60] , [61] , [62] , 53 , 47 , 56 , 45 ]). Green – data indicating lysosomotropism; orange – data indicating cardiotoxicity and hepatotoxicity; blue – data indicating safety; grey – approved drugs; yellow – data indicating broad spectrum antiviral effects; +* - drugs approved only in some countries; n.d. – no data.…”

Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice

“…In particular, the product RO5657 (a CCR5 antagonist used as an anti-HIV treatment) has been shown to be pro-arrhythmogenic in cynomolgus monkeys via the inhibition of multiple cardiac channels (28). On the other hand, treatment with vicriviroc (another CCR5 antagonist) also in combination with HIV protease inhibitors was not shown to induce a clinically relevant QT prolongation in healthy humans (in a randomised phase I study) (29). A potential pro-arrhythmogenic effect of Evasin treatments was not assessed in our study.…”

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

“…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.…”