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Taylor, Justin; Cox-North, Paula; Landis, Charles
doi: 10.1007/s40265-016-0658-0pmid: 27878476
Cirrhosis due to chronic hepatitis C (HCV) is the leading indication for liver transplantation in North America and Europe. HCV re-infection post-transplant is nearly universal and if left untreated negatively affects patient and graft survival. Until recently, treatment options for HCV were limited to interferon (IFN)-based therapies which had low sustained viral response (SVR) rates and were poorly tolerated in the post-transplant setting. In the last 3 years, the promise of the directly acting antivirals (DAAs) for the treatment of HCV has been fulfilled with high sustained viral response (SVR) rates and a low side effect profile demonstrated in both registration trials and real-world studies. This innovation has allowed post-liver transplant patients with HCV recurrence access to interferon-free therapies with extraordinary efficacy, safety, tolerability, and fewer drug–drug interactions.
doi: 10.1007/s40265-016-0663-3pmid: 27988869
Since the introduction of the serotonin 5-hydroxy tryptamine 3 (5-HT3) receptor antagonists in the early 1990s, the incidence of postoperative nausea and vomiting (PONV) and post-discharge nausea and vomiting (PDNV) has decreased, yet continues to be a problem for the surgical patient. The clinical application of the 5-HT3 receptor antagonists has helped define the approach and role of these antiemetics in the prevention and treatment of PONV and PDNV. Pharmacological and clinical differences exist among these medications resulting in corresponding differences in effectiveness, safety, optimal dosage, time of administration, and use as combination and rescue antiemetic therapy. The clinical application of the 5-HT3 receptor antagonist antiemetics has improved the prevention and treatment of PONV and PDNV. The most recent consensus guidelines for PONV published in 2014 outline the use of these antiemetics. The 5-HT3 receptor antagonists play an important role to help prevent PONV and PDNV in perioperative care pathways such as Enhanced Recovery After Surgery (ERAS). Comparisons and guidelines for use of the 5-HT3 receptor antagonists in relation to the risk for PONV and PDNV are reviewed.
Zhanel, George; Hartel, Erika; Adam, Heather; Zelenitsky, Sheryl; Zhanel, Michael; Golden, Alyssa; Schweizer, Frank; Gorityala, Bala; Lagacé-Wiens, Philippe; Walkty, Andrew; Gin, Alfred; Hoban, Daryl; Lynch, Joseph; Karlowsky, James
Lamb, Yvette; Garnock-Jones, Karly; Keam, Susan
doi: 10.1007/s40265-016-0660-6pmid: 27832472
Oxycodone DETERx ® extended-release (ER) capsules (Xtampza® ER), an abuse-deterrent formulation of oxycodone as the myristate salt, are approved in the USA for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. This narrative review discusses the clinical efficacy and tolerability of the oxycodone DETERx ® ER capsule formulation in the management of severe pain, and provides an overview of pharmacokinetics, abuse-deterrent properties and alternative administration options. The microsphere-in-capsule DETERx ® drug delivery platform allows administration via sprinkle-dosing or enteral tubes. The physicochemical properties of the formulation make it difficult to manipulate and its ER pharmacokinetic profile is retained after crushing or chewing. Clinical abuse-potential studies suggest these properties may translate to reduced intranasal abuse, with implications for abuse via the oral route less certain. The efficacy of oxycodone DETERx ® ER in the management of moderate to severe, chronic pain was demonstrated in a well designed, phase III trial, in which it was more effective than placebo at reducing pain intensity. The formulation was generally well tolerated in this trial; the most common treatment-emergent adverse events were nausea and constipation. As an opioid, oxycodone DETERx ® ER carries risks of addiction, abuse and misuse. Post-marketing epidemiological studies will be necessary in determining the impact of oxycodone DETERx ® on oxycodone abuse liability. Nevertheless, oxycodone DETERx ® ER is a useful treatment option for patients with severe, chronic pain, particularly when comorbid dysphagia or difficulty swallowing is a concern.
Al-Salama, Zaina; Keating, Gillian
doi: 10.1007/s40265-016-0661-5pmid: 27909994
The multiple tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx™) is approved in the USA for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy. In the EU, cabozantinib is indicated for the treatment of advanced RCC in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. In adults with advanced or metastatic clear-cell RCC who had previously received VEGF receptor (VEGFR) TKIs, progression-free survival (PFS) and overall survival (OS) were significantly prolonged in patients who received oral cabozantinib versus oral everolimus in the pivotal METEOR trial. Objective response was achieved in a significantly higher proportion of patients receiving cabozantinib than those receiving everolimus. Cabozantinib had a manageable adverse events profile in patients with advanced RCC. Thus, cabozantinib is an important new option for use in patients with advanced RCC who have previously received antiangiogenic therapy.
doi: 10.1007/s40265-016-0664-2pmid: 27915445
An extended-release (ER) subcutaneously injectable formulation of the first-generation 5-HT3 receptor antagonist granisetron is now available in the USA (Sustol®), where it is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide combination chemotherapy regimens in adults. Granisetron ER is administered as a single subcutaneous injection and uses an erosion-controlled drug-delivery system to allow prolonged granisetron release. Primary endpoint data from phase III studies after an initial cycle of chemotherapy indicate that, when used as part of an antiemetic regimen, granisetron ER injection is more effective than intravenous ondansetron in preventing delayed CINV following highly emetogenic chemotherapy (HEC); is noninferior to intravenous palonosetron in preventing both acute CINV following MEC or HEC and delayed CINV following MEC; and is similar, but not superior, to palonosetron in preventing delayed CINV following HEC. The benefits of granisetron ER were seen in various patient subgroups, including those receiving anthracycline plus cyclophosphamide-based HEC, and (in an extension of one of the studies) over multiple MEC or HEC cycles. Granisetron ER injection is generally well tolerated, with an adverse event profile similar to that of ondansetron or palonosetron. Thus, granisetron ER injection expands the options for preventing both acute and delayed CINV in adults with cancer receiving MEC or anthracycline plus cyclophosphamide-based HEC.
doi: 10.1007/s40265-016-0671-3pmid: 27900648
Etelcalcetide (Parsabiv™) is a novel second generation calcimimetic agent developed by Amgen for the treatment of secondary hyperparathyroidism (SHPT), a complication of chronic kidney disease (CKD). Etelcalcetide reduces circulating levels of parathyroid hormone and calcium by binding directly to the calcium-sensing receptor. Intravenous etelcalcetide has been approved in the EU for the treatment of SHPT in adult patients with CKD on haemodialysis therapy. Regulatory applications for etelcalcetide in SHPT are also under review in the USA and Japan. This article summarizes the milestones in the development of etelcalcetide leading to this first global approval for the treatment of SHPT.
doi: 10.1007/s40265-016-0673-1pmid: 27905086
Bezlotoxumab (Zinplava™) is a human monoclonal antibody against Clostridium difficile toxin B developed by Merck & Co. In October 2016 it was approved in the USA for reducing the recurrence of C. difficile infection. This article summarizes the milestones in the development of bezlotoxumab leading to this first approval for use in patients receiving antibacterial drug treatment for C. difficile infection who are at high risk for recurrence of C. difficile infection.
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doi: 10.1007/s40265-016-0667-zpmid: 27909995
Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation. However, unlike telithromycin, which binds to two sites on the ribosome, solithromycin has three distinct ribosomal binding sites. Its desosamine sugar interacts at the A2058/A2059 cleft in domain V (as all macrolides do), an extended alkyl-aryl side chain interacts with base pair A752-U2609 in domain II (similar to telithromycin), and a fluorine at C-2 of solithromycin provides additional binding to the ribosome. Studies describing solithromycin activity against Streptococcus pneumoniae have reported that it does not induce erm-mediated resistance because it lacks a cladinose moiety, and that it is less susceptible than other macrolides to mef-mediated efflux due to its increased ribosomal binding and greater intrinsic activity. Solithromycin has demonstrated potent in vitro activity against the most common CABP pathogens, including macrolide-, penicillin-, and fluoroquinolone-resistant isolates of S. pneumoniae, as well as Haemophilus influenzae and atypical bacterial pathogens. Solithromycin displays multi-compartment pharmacokinetics, a large volume of distribution (>500 L), approximately 67% bioavailability when given orally, and serum protein binding of 81%. Its major metabolic pathway appears to follow cytochrome P450 (CYP) 3A4, with metabolites of solithromycin undergoing biliary excretion. Its serum half-life is approximately 6–9 h, which is sufficient for once-daily administration. Pharmacodynamic activity is best described as fAUC0–24/MIC (the ratio of the area under the free drug concentration–time curve from 0 to 24 h to the minimum inhibitory concentration of the isolate). Solithromycin has completed one phase II and two phase III clinical trials in patients with CABP. In the phase II trial, oral solithromycin was compared with oral levofloxacin and demonstrated similar clinical success rates in the intention-to-treat (ITT) population (84.6 vs 86.6%). Clinical success in the clinically evaluable patients group was 83.6% of patients receiving solithromycin compared with 93.1% for patients receiving levofloxacin. In SOLITAIRE-ORAL, a phase III trial which assessed patients receiving oral solithromycin or oral moxifloxacin for CABP, an equivalent (non-inferior) early clinical response in the ITT population was demonstrated for patients receiving either solithromycin (78.2%) or moxifloxacin (77.9%). In a separate phase III trial, SOLITAIRE-IV, patients receiving intravenous-to-oral solithromycin (79.3%) demonstrated non-inferiority as the primary outcome of early clinical response in the ITT population compared with patients receiving intravenous-to-oral moxifloxacin (79.7%). Overall, solithromycin has been well tolerated in clinical trials, with gastrointestinal adverse events being most common, occurring in approximately 10% of patients. Transaminase elevation occurred in 5–10% of patients and generally resolved following cessation of therapy. None of the rare serious adverse events that occurred with telithromycin (i.e., hepatotoxicity) have been noted with solithromycin, possibly due to the fact that solithromycin (unlike telithromycin) does not possess a pyridine moiety in its chemical structure, which has been implicated in inhibiting nicotinic acetylcholine receptors. Because solithromycin is a possible substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp), it may display drug interactions similar to macrolides such as clarithromycin. Overall, the in vitro activity, clinical efficacy, tolerability, and safety profile of solithromycin demonstrated to date suggest that it continues to be a promising treatment for CABP.