Drugs

Perlin, David

doi: 10.1007/s40265-014-0286-5pmid: 25255923

This article addresses the emergence of echinocandin resistance among Candida species, mechanisms of resistance, factors that promote resistance and confounding issues surrounding standard susceptibility testing. Fungal infections remain a significant cause of global morbidity and mortality, especially among patients with underlying immunosupression. Antifungal therapy is a critical component of patient management for acute and chronic diseases. Yet, therapeutic choices are limited due to only a few drug classes available to treat systemic disease. Moreover, the problem is exacerbated by the emergence of antifungal resistance, which has resulted in difficult to manage multidrug resistant strains. Echinocandin drugs are now the preferred choice to treat a range of candidiasis. These drugs target and inhibit the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a key cell wall polymer. Therapeutic failures involving acquisition of resistance among susceptible organisms like Candida albicans is largely a rare event. However, in recent years, there is an alarming trend of increased resistance among strains of Candida glabrata, which in many cases are also resistant to azole drugs. Echinocandin resistance is always acquired during therapy and the mechanism of resistance is well established to involve amino acid changes in “hot-spot” regions of the Fks subunits carrying the catalytic portion of glucan synthase. These changes significantly decrease the sensitivity of the enzyme to drug resulting in higher MIC values. A range of drug responses, from complete to partial refractory response, is observed depending on the nature of the amino acid substitution, and clinical responses are recapitulated in pharmacodynamic models of infection. The cellular processes promoting the formation of resistant Fks strains involve complex stress response pathways, which yield a variety of adaptive compensatory genetic responses. Stress-adapted cells become drug tolerant and can form stable drug resistant FKS mutations with continued drug exposure. A major concern for resistance detection is that classical broth microdilution techniques show significant variability among clinical microbiology laboratories for certain echinocandin drugs and Candida species. The consequence is that susceptible strains are misclassified according to established clinical breakpoints, and this has led to confusion in the field. Clinical factors that appear to promote echinocandin resistance include the expanding use of antifungal agents for empiric therapy and prophylaxis. Furthermore, host reservoirs such as biofilms in the gastrointestinal tract or intra-abdominal infections can seed development of resistant organisms during therapy. A fundamental understanding of the primary molecular resistance mechanism, along with cellular and clinical factors that promote resistance emergence, is critical to develop better diagnostic tools and therapeutic strategies to overcome and prevent echinocandin resistance.

Trujillo, Toby; Dobesh, Paul

doi: 10.1007/s40265-014-0278-5pmid: 25178252

Target-specific oral anticoagulants have become increasingly available as alternatives to traditional agents for the management of a number of thromboembolic disorders. To date, the direct Factor Xa inhibitor rivaroxaban is the most widely approved of the new agents. The dosing of rivaroxaban varies and adheres to specific schedules in each of the clinical settings in which it has been investigated. These regimens were devised based on the results of phase II dose-finding studies and/or pharmacokinetic modeling, and were demonstrated to be successful in randomized, phase III studies. In most cases, the pharmacodynamic profile of rivaroxaban permits once-daily dosing. A once-daily dose is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery, the long-term prevention of stroke in patients with non-valvular atrial fibrillation, and the long-term secondary prevention of recurrent VTE. Twice-daily dosing is required in the acute phase of treatment in patients with VTE and in the combination of rivaroxaban with standard single or dual antiplatelet therapy for secondary prevention after acute coronary syndrome events. This article reviews the empirical and clinical rationale supporting the dose regimens of rivaroxaban in each clinical setting.

Mohty, Mohamad; Bacigalupo, Andrea; Saliba, Faouzi; Zuckermann, Andreas; Morelon, Emmanuel; Lebranchu, Yvon

doi: 10.1007/s40265-014-0277-6pmid: 25164240

In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin® was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.

Murphy, Lorraine; Rennard, Stephen; Donohue, James; Molimard, Mathieu; Dahl, Ronald; Beeh, Kai-Michael; Dederichs, Juergen; Fülle, Hans-Jürgen; Higgins, Mark; Young, David

doi: 10.1007/s40265-014-0284-7pmid: 25212789

Sanford, Mark

doi: 10.1007/s40265-014-0271-zpmid: 25060982

OnabotulinumtoxinA (BOTOX®) is a type A neurotoxin derived from Clostridium botulinum bacteria that is approved as treatment for urinary incontinence (UI) in patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) or subcervical spinal cord injury (SCI) who are not adequately treated by antimuscarinics. This article reviews the pharmacology of intradetrusor onabotulinumtoxinA in this indication. The presumed mode of action of onabotulinumtoxinA in bladder disorders is by interfering with efferent innervation of the detrusor muscle and afferent pathways involved in the micturition reflex. In phase III trials in adult patients with MS or SCI with UI who were not adequately treated with antimuscarinics, intradetrusor onabotulinumtoxinA 200 U produced significantly greater mean changes (reductions) from baseline in UI episodes/week at week 6 than placebo (primary endpoint). Similar significant benefits of intradetrusor onabotulinumtoxinA 200 U over placebo were observed on other UI, urodynamic, health-related quality of life and treatment satisfaction endpoints. Intradetrusor onabotulinumtoxinA 200 U was generally well tolerated, with the most frequent adverse events being urinary tract infections and urinary retention. Few patients discontinued treatment because of adverse events. Based on interim analyses of an extension study of the phase III trials, repeat injections of onabotulinumtoxinA 200 U were similarly efficacious and well tolerated. Intradetrusor onabotulinumtoxinA represents a clinically important advance in the therapy of UI in patients with MS or SCI who have not responded to antimuscarinics or who are unable to tolerate antimuscarinics.

Burness, Celeste; Dhillon, Sohita; Keam, Susan

doi: 10.1007/s40265-014-0283-8pmid: 25193626

Lanreotide Autogel® (ATG) [Somatuline® Autogel®, Somatuline® Depot®] is a prolonged-release, supersaturated aqueous gel formulation of the somatostatin analogue lanreotide acetate that acts via somatostatin receptors to reduce both growth hormone and insulin-like growth factor-I levels. It is indicated for the treatment of patients with acromegaly who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. This article reviews the clinical efficacy and tolerability of lanreotide ATG in the treatment of acromegaly, as well as summarizing its pharmacological properties. Results of clinical trials and extension studies of up to 4 years duration showed that deep subcutaneous lanreotide ATG was a generally effective treatment in treatment-naive and treatment-experienced adults with acromegaly. Lanreotide ATG provided hormonal control and improved both health-related quality of life and acromegaly symptoms in most patients; it also reduced tumour volume to a clinically significant extent in studies of primary therapy. Moreover, lanreotide ATG was generally no less effective than intramuscular lanreotide long-acting microparticles and was as effective as intramuscular octreotide long-acting release in switching or crossover studies, including those with standard or extended dosing intervals. Lanreotide ATG is generally well tolerated; the most frequently reported adverse events were mild or moderate transient gastrointestinal symptoms. Lanreotide ATG also has the advantage of being available in a convenient pre-filled syringe and is given subcutaneously rather than intramuscularly. Thus, lanreotide ATG continues to be a valuable option in the treatment of acromegaly, with potential advantages being ease of administration and longer dosing intervals in patients who have an adequate response to initial therapy.

McCormack, Paul

doi: 10.1007/s40265-014-0290-9pmid: 25217402

Omalizumab (Xolair®) is a humanized, recombinant, IgG, anti-IgE monoclonal antibody that binds to the Fc region of free IgE and prevents it from binding to its high-affinity receptor (FcεR1) on mast cells and basophils. This reduction in free IgE leads to a reduction in mast cell/basophil degranulation and the release of histamine, and to the down-regulation of FcεR1 receptors on these cells. Omalizumab does not bind to cell-bound IgE or to IgG. In well-controlled clinical trials in patients with chronic spontaneous urticaria and persistent symptoms despite background treatment with antihistamines, add-on therapy with subcutaneous omalizumab 300 mg every 4 weeks for 12 or 24 weeks significantly reduced the severity of itching, and the number and size of hives, and increased patients’ health-related quality of life and the proportion of days free from angioedema compared with placebo. Subcutaneous omalizumab was generally well tolerated; the incidence and severity of adverse events in omalizumab recipients were similar to those in placebo recipients, and most adverse events were of mild or moderate severity. The only adverse events occurring more frequently with omalizumab than with placebo during treatment in a safety study were headache and upper respiratory tract infection. Thus, omalizumab is an effective and well-tolerated add-on therapy in patients with chronic spontaneous urticaria who are symptomatic despite background therapy with H1 antihistamines.

Markham, Anthony

doi: 10.1007/s40265-014-0285-6pmid: 25187123

Idelalisib (Zydelig®) is a highly specific small-molecule phosphatidylinositol-3-kinase (PI3Kδ) inhibitor that has been developed as an oral treatment for B cell haematological cancers. It has received its first approval in the US in July 2014 for the treatment of relapsed chronic lymphocytic leukaemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (NHL) and relapsed small lymphocytic leukaemia (SLL). Idelalisib is under regulatory review in the EU—where it has received a positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use—and in clinical development for CLL in Australia and Canada. This article summarizes the milestones in the development of Idelalisib leading to this first approval for relapsed CLL, NHL and SLL.

Ryan, Nicola

doi: 10.1007/s40265-014-0287-4pmid: 25193627

Nonsense mutations are implicated in 5–70 % of individual cases of most inherited diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren (Translarna™) is an orally available, small molecule compound that targets nonsense mutations, and is the first drug in its class. Ataluren appears to allow cellular machinery to read through premature stop codons in mRNA, enabling the translation process to produce full-length, functional proteins. This article summarizes the milestones in the development of ataluren leading to its conditional first approval for nonsense mutation DMD.

Wendling, Daniel; Prati, Clément

doi: 10.1007/s40265-014-0288-3pmid: 25223824