Drugs
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Eltrombopag (Promacta®) is an orally active thrombopoietin receptor agonist recently approved in the US for the treatment of patients with severe aplastic anaemia who have had an insufficient response to immunosuppressive therapy. This article reviews the efficacy and tolerability of eltrombopag in this indication and overviews its pharmacological properties. Eltrombopag does not compete with thrombopoietin and binds to a different site on the receptor, producing additive effects. ⋯ In robust responders, stable haematological counts were maintained after eltrombopag discontinuation. Eltrombopag was generally well tolerated, with increased liver transaminases as the only dose-limiting toxicity. Clonal cytogenetic abnormalities were observed in 19 % of patients and dysplasia in 5 % of patients.
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Review
Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection.
A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. ⋯ Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.
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Palbociclib (Ibrance®) is an oral, reversible, selective, small-molecule inhibitor of cyclin-dependent kinases (CDK) 4 and CDK6 developed by Pfizer for the treatment of cancer. CDKs are important modulators of cell cycle entry and progression in response to growth signals, and inhibition of these kinases with palbociclib could enhance the activity of other anticancer drugs in tolerable regimens. ⋯ A phase II trial is underway in the USA for non-small cell lung cancer under a US National Cancer Institute-funded research collaboration, and several phase I and II investigations are being conducted for various other solid tumour types and haematological malignancies. This article summarizes the milestones in the development of palbociclib leading to this first approval for use in postmenopausal women with estrogen-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.
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Lenvatinib (Lenvima™) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor α, RET and KIT. In addition to their role in normal cellular function, these kinases have been implicated in pathogenic angiogenesis, tumour growth and cancer progression. Lenvatinib is being developed by Eisai Co. ⋯ Lenvatinib has orphan designation in the EU and Japan for use in differentiated thyroid cancer. In addition, an ongoing global, phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma. This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.
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The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor ledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir (ledipasvir/sofosbuvir; Harvoni(®)) was recently approved in the US and the EU. The phase III ION trials included treatment-naive (ION-1 and -3) or treatment-experienced (ION-2) patients with chronic HCV genotype 1 infection (≈20 % of patients in ION-1 and -2 had cirrhosis, whereas no patient in ION-3 had cirrhosis). A sustained virological response 12 weeks' post-treatment (SVR12) was seen in 99 % of treatment-naive patients receiving ledipasvir/sofosbuvir for 12 weeks in ION-1, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. ⋯ Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infection, in HCV and HIV co-infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Oral ledipasvir/sofosbuvir was generally well tolerated. In conclusion, ledipasvir/sofosbuvir is an important new single-tablet regimen that represents a significant advance in the treatment of chronic hepatitis C.