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Keating G.M.,Adis 41 Centorian Drive
Drugs | Year: 2014

Afatinib (Gilotrif™, Giotrif®) is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases. Afatinib downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. The objective response rate was significantly higher with afatinib than with pemetrexed plus cisplatin or gemcitabine plus cisplatin, and patient-reported outcomes for symptoms such as cough and dyspnoea and certain health-related quality of life measures significantly favoured afatinib versus pemetrexed plus cisplatin or gemcitabine plus cisplatin. Afatinib also showed efficacy in EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations who had received no more than one prior chemotherapy regimen for advanced disease, according to the results of the noncomparative, multinational, phase II LUX-Lung 2 trial. Oral afatinib had a manageable tolerability profile. EGFR-mediated adverse events (e.g. diarrhoea, rash/acne) were generally managed using dose reduction and delays. In conclusion, afatinib is a valuable new option for use in treatment-naïve or EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations. © 2014 Springer International Publishing Switzerland. Source


Keating G.M.,Adis 41 Centorian Drive
CNS Drugs | Year: 2013

The opioid system modulator nalmefene (Selincro®) is approved in the EU for as-needed use to reduce alcohol consumption in alcohol-dependent adults with a high drinking risk level. This article reviews the efficacy and tolerability of as-needed oral nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. In two randomized, double-blind, multinational trials (ESENSE 1 and ESENSE 2), as-needed nalmefene significantly reduced the number of heavy drinking days (in both trials) and total alcohol consumption (in ESENSE 1) at month 6. In the randomized, double-blind, multinational SENSE trial, as-needed nalmefene significantly improved both of these endpoints at month 13, but not at month 6. As-needed nalmefene had a greater beneficial effect in the target population (i.e. alcohol-dependent patients with at least a high drinking risk level at screening and randomization), with post hoc analyses revealing significant reductions in both the number of heavy drinking days and total alcohol consumption at month 6 (in ESENSE 1 and ESENSE 2) and at month 13 (in SENSE). Oral nalmefene was generally well tolerated in patients with alcohol dependence, with the most commonly occurring adverse events including nausea, insomnia and dizziness. In conclusion, as-needed nalmefene provides an important new option for use in the treatment of alcohol dependence. © 2013 Springer International Publishing Switzerland. Source


Trastuzumab emtansine (Kadcyla™) is an antibody-drug conjugate consisting of the humanized anti-human epidermal growth factor receptor (HER) 2 antibody trastuzumab covalently linked to the highly potent microtubule inhibitory drug DM1 (a cytotoxic derivative of maytansine) via a stable thioether linker. Intravenous trastuzumab emtansine was recently approved for use in patients with HER2-positive, unresectable, locally advanced (in the EU) or metastatic (in the USA and EU) breast cancer who had previously received trastuzumab and a taxane (separately or in combination), making it the first antibody-drug conjugate approved in this indication. This article reviews the efficacy and tolerability of trastuzumab emtansine in these patients and summarizes its pharmacology. In the well-designed EMILIA study, trastuzumab emtansine significantly prolonged progression-free survival and overall survival, relative to treatment with lapatinib plus capecitabine, in patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Trastuzumab emtansine was generally well tolerated in this study, with <6 % of patients discontinuing treatment because of adverse events. Based on its efficacy and favourable tolerability, the US National Comprehensive Cancer Network guidelines recommend trastuzumab emtansine as the preferred option in patients with HER2-positive metastatic breast cancer who have received previous trastuzumab-based therapy. © 2014 Springer International Publishing Switzerland. Source


Deeks E.D.,Adis 41 Centorian Drive
Drugs | Year: 2014

The HIV integrase inhibitor elvitegravir is now available as a single-agent tablet (Vitekta®) in the EU, where it is indicated for once-daily oral use, in combination with a ritonavir-boosted protease inhibitor (PI) and other antiretrovirals, for the treatment of HIV-1 infection in adults without known mutations associated with resistance to elvitegravir. The drug has potent anti-HIV activity and a well characterized resistance profile, although cross resistance with raltegravir is observed. When used in combination with ritonavir-boosted PI-based antiretroviral therapy (ART) in treatment-experienced adults in a randomized, double-blind, phase III trial, once-daily elvitegravir was associated with virological suppression noninferior to that seen with twice-daily raltegravir after 48 weeks' treatment, and such benefits were largely maintained at 96 weeks. Moreover, in an open-label extension of this study, in which all patients received an elvitegravir regimen, virological suppression continued to be observed in most patients at 144 weeks. Elvitegravir is generally well tolerated, with diarrhoea and nausea being the most common tolerability issues. Thus, single-agent elvitegravir extends the treatment options available for use in the ritonavir-boosted PI-based ART regimens of adults infected with HIV-1 and has the convenience of once-daily administration. © 2014 Springer International Publishing Switzerland. Source


Cobicistat (Tybost™) is a mechanism-based inhibitor of cytochrome P450 (CYP) 3A enzymes that is indicated in the EU as a pharmacokinetic enhancer (i.e. booster) of the HIV-1 protease inhibitors (PIs) atazanavir and darunavir in adults. Cobicistat has a lower potential for off-target drug interactions than the standard boosting agent ritonavir, due to its more selective inhibition of CYP3A and lower likelihood for enzymatic induction, and is devoid of anti-HIV activity. When used to boost darunavir or atazanavir in healthy volunteers, oral cobicistat 150 mg once daily provided bioequivalent PI exposure to that seen with oral ritonavir 100 mg once daily (i.e. low-dose ritonavir). Moreover, in treatment-naïve adults infected with HIV-1 participating in a large, double-blind, phase III trial, an atazanavir-based antiretroviral regimen boosted with cobicistat 150 mg once daily provided a high rate of virological suppression after 48 weeks of therapy that was noninferior to that seen with low-dose ritonavir boosting. Cobicistat was generally well tolerated in this study, with a tolerability profile similar to that of ritonavir. Cobicistat may increase serum creatinine levels (possibly via inhibition of proximal renal tubular cell transporters) and thus reduce estimated glomerular filtration rate (GFR), although it does not appear to affect actual GFR. The drug is more soluble than ritonavir, making coformulation easier, and fixed-dose formulations combining cobicistat with darunavir and atazanavir are in development. Thus, cobicistat is an emerging alternative to ritonavir for the pharmacokinetic enhancement of PIs in adults with HIV-1 infection. © 2013 Springer International Publishing Switzerland. Source

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