Drugs
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Review
Dolutegravir: a review of its use in the management of HIV-1 infection in adolescents and adults.
Dolutegravir (Tivicay(®)) is a new-generation HIV-1 integrase strand transfer inhibitor recently approved in the EU and Japan for the treatment of HIV-1 infection in adolescents and adults in combination with other antiretroviral drugs. It is suitable for once-daily administration and achieves therapeutic concentrations without the need for pharmacokinetic boosting. It has a high barrier to resistance and is generally active against viral strains resistant to first-generation integrase inhibitors. ⋯ Dolutegravir was also effective in a high proportion of patients failing on raltegravir- or elvitegravir-based therapy as a result of integrase resistance mutations. Dolutegravir was generally well tolerated, with the vast majority of adverse events being mild or moderate in intensity; serious adverse events were uncommon. Therefore, dolutegravir is an important new addition to the expanding list of antiretroviral drugs for treating HIV-1 infection in adults and adolescents.
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Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. ⋯ The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options.
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Nivolumab (Opdivo(®)) is a fully human monoclonal antibody against programmed death receptor-1, a negative regulatory checkpoint molecule with a role in immunosuppression. The drug is administered intravenously and is approved for the treatment of unresectable malignant melanoma in Japan. The potential for intravenous nivolumab to be used in the treatment of advanced malignancies such as melanoma was initially demonstrated in phase I dose-ranging trials. ⋯ The clinical benefit of the drug was durable, with patients surviving free from progression for a median of 172 days and median overall survival not yet reached. Nivolumab had an acceptable tolerability profile in this trial, with fewer than 18 % of patients experiencing grade 3 or 4 adverse events related to the drug, the most common of which was increased γ-glutamyl transferase. Thus, nivolumab is an emerging, promising option for the treatment of malignant melanoma.
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Vedolizumab [Entyvio(®) (US, Europe)], a humanized monoclonal antibody α4β7 integrin receptor antagonist, has been developed by Millennium Pharmaceuticals (d/b/a Takeda Pharmaceuticals International) for the treatment of ulcerative colitis and Crohn's disease. Vedolizumab has received its first global approval for the treatment of ulcerative colitis and Crohn's disease in the US, for use in adult patients with moderate-to-severe disease who have had an inadequate response, loss of response or intolerance to one or more standard therapies (corticosteroids, immunomodulators or tumour necrosis factor-α inhibitor) or demonstrated dependence on corticosteroids. Vedolizumab has since been approved for ulcerative colitis and Crohn's disease in the EU, Norway, Iceland and Liechtenstein. This article summarizes the milestones in the development of vedolizumab leading to its first approval for the treatment of ulcerative colitis and Crohn's disease.
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Certolizumab pegol (Cimzia(®)) is a polyethylene glycolylated antigen-binding fragment of a recombinant human monoclonal antibody that binds to and selectively neutralizes tumour necrosis factor (TNF) α. In the EU, subcutaneous certolizumab pegol is indicated for the treatment of adults with severe active axial spondyloarthritis (axSpA), comprising ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA), and for adults with active psoriatic arthritis (PsA). In the USA it is indicated for the treatment of adults with active AS or active PsA. ⋯ In addition, 12 weeks' treatment with certolizumab pegol reduced inflammation in the sacroiliac joints and spine in patients with axSpA and 24 weeks' treatment with the agent slowed radiographic disease progression in patients with PsA. Certolizumab pegol was generally well tolerated in these studies, with a tolerability profile consistent with that seen in previous clinical trials in other indications. Although additional long-term and comparative data are needed to position certolizumab pegol with respect to other TNFα antagonists, current evidence indicates that certolizumab pegol is an effective option for the treatment of axSpA (including AS and nr-axSpA) and PsA.