Naloxegol,a new drug for the treatment of opioid-induced constipation

Introduction: With increasing chronic opioid use, opioid-induced constipation (OIC) is becoming a relevant clinical challenge. Presently, only few treatments have been demonstrated to be more effective than placebo in treating OIC but most of them have a restricted clinical application because of side effects. Naloxegol, an orally administered, peripherally acting, μ-opioid receptor antagonist (PAMORA), was developed for the treatment of OIC.

Area covered: This review summarizes published information and presentations at meetings on the effects of naloxegol in OIC. Pharmacodynamic studies have demonstrated that naloxegol inhibits gastrointestinal opioid effects while preserving central analgesic actions. Phase II and Phase III studies in patients with non-cancer OIC have confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. Adverse events were mainly gastrointestinal in origin and usually transient and mild. There were no signs of opioid withdrawal in the studies. Safety and tolerability were also shown in a long-term safety study. Regulatory authorities have recently approved the use of naloxegol in OIC.

Expert opinion: Naloxegol is the first approved, orally available PAMORA. The drug has the potential to substantially improve management of OIC patients.     

Cebranopadol: a first-in-class potent analgesic agent with agonistic activity at nociceptin/orphanin FQ and opioid receptors

Introduction: Pain is a syndrome of various clinical disorders, which arises from various pathological conditions and which presents significant challenges in both its diagnosis and treatment. There is currently a strong medical demand to develop new therapies with a higher efficacy and a better tolerability profile.

Areas covered: In this review, the authors report on the available data for the pharmacological properties of cebranopadol (GRT6005), a first in-class, potent analgesic compound which acts as an agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors. They highlight the in vitro receptor binding studies, as well as the in vivo preclinical results on the analgesic efficacy of cebranopadol obtained in several rodent pain models. The authors also briefly summarize the available data from clinical trials with cebranopadol.

Expert opinion: Cebranopadol displays analgesic, antiallodynic and antihyperalgesic properties in several rat models of acute nociceptive, inflammatory, cancer and neuropathic pain. In contrast to classical opioids, it has a higher analgesic potency in models of neuropathic pain than in acute nociceptive pain. Even at higher analgesic doses, cebranopadol does not induce motor coordination deficits or respiratory depression in rats. Hence, it seems to possess a broader therapeutic window than classical opioids. While it is particularly interesting as a novel, potent bifunctional agonist of NOP/opioid receptors, the outcome of its ongoing and planned clinical trials will be crucial for its future development and potential application in humans.     

Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C

Introduction: The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy.

Areas Covered: The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available.

Expert Opinion: In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug–drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug–drug interactions.     

Apatinib for the treatment of gastric cancer

Introduction: Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients.

Areas covered: The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo.

Expert opinion: Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance.     

Evaluation of dolutegravir safety for the treatment of HIV-1

Introduction: Dolutegravir (DGV) is the newest integrase inhibitor approved for the treatment of HIV-1 infection in both treatment-naive and experienced adults and adolescents. This article reviews the safety of DGV for the treatment of HIV-1 infection.

Areas covered: The PubMed database was searched using the keywords ‘DGV’ and ‘HIV’. In addition, conference proceedings from Conference on Retroviruses and Opportunistic Infections, International AIDS Society and European AIDS Clinical Society meetings were searched for presentations on DGV clinical studies.

Expert opinion: DGV has demonstrated a favorable safety profile and is well tolerated for the treatment of HIV-1 infection. Unlike raltegravir, DGV can be given once daily, and unlike elvitegravir, it does not require pharmacologic boosting to achieve consistent blood levels.     

Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis

Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials.

Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug.

Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.     

Adefovir dipivoxil in chronic hepatitis B: history and current uses

Introduction: Sodium oxybate (SMO) has been shown to be safe and effective in the treatment of patients with alcohol use disorders (AUDs); it was approved in Italy and Austria for the treatment of alcohol withdrawal syndrome and for relapse prevention. The focus of this review is to discuss the clinical evidence on the therapeutic potential of SMO for AUDs.

Areas covered: This review covers the studies in patients with alcohol withdrawal syndrome who received SMO for the treatment of withdrawal symptoms and the studies in patients with AUDs who received SMO to achieve total alcohol abstinence, reduction of alcohol intake, and relapse prevention. Relevant medical literature on SMO was identified by searching databases including MEDLINE and EMBASE (searches last updated 20 September 2013), bibliographies from published literature, clinical trial registries/databases, and websites.

Expert opinion: SMO has proved safe and effective in the treatment of alcohol withdrawal syndrome and in the prevention of relapses. Craving for and abuse of SMO have been reported, in particular in some subtypes of alcoholic patients, e.g., those affected by co-addiction and/or psychiatric comorbidity. Future multicenter, multinational, randomized clinical trials should be useful to optimize the treatments in relation with patients' characteristics, for example, pharmacogenetic, neurobiological, and psychological.     

Odanacatib for the treatment of osteoporosis

Introduction: Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib, are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue.

Areas covered: The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib.

Expert opinion: Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.     

Not everything about atrial fibrillation is a hot topic: drug-induced atrial fibrillation is an exception

Introduction: Amphotericin B (AmB) was first approved by the US Food and Drug Administration in 1959 with sodium deoxycholate (DAmB, Fungizone®). Extensive toxicities associated with the drug led to the development of lipid formulations of AmB, including liposomal amphotericin B (L-AmB, AmBisome®). Phase I studies as well as comparative Phase III clinical trials indicate that L-AmB is associated with less nephrotoxicity and reduced infusion-related toxicity. There is, however, no recent comprehensive review of the safety and tolerability of L-AmB.

Areas covered: This article reviews the safety, tolerability and the mechanisms of the major toxicities associated with L-AmB, including nephrotoxicity, infusion-related reactions (IRRs), anemia and thrombocytopenia, and hepatic abnormalities. The article further discusses the mechanism of action and pharmacokinetics of L-AmB.

Expert opinion: L-AmB is a broad-spectrum antifungal agent that has significantly reduced toxicities compared to its predecessor, DAmB.     

Blinatumomab for the treatment of B-cell lymphoma

Introduction: Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens. Among the various formats of bispecific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or costimulation. Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL).

Areas covered: This article reviews the current literature on blinatumomab including its pharmacology, preclinical findings, clinical trials in B-cell NHL and, to a lesser extent, Phase II studies in B-ALL. The authors discuss the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market.

Expert opinion: The recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers. Although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches. Larger trials are needed to demonstrate blinatumomab’s curative potential in aggressive histologies.     

The clinical safety of ibrutinib in chronic lymphocytic leukemia

Introduction: Ibrutinib, a targeted inhibitor of B-cell receptor signaling, achieved impressive clinical results for patients with chronic lymphocytic leukemia (CLL). These results allowed the approval of ibrutinib for the treatment of patients with CLL who have received at least one prior therapy and those with a 17p deletion regardless of line of therapy.

Areas covered: Comprehensive data from either Phase I-II or randomized Phase III studies are analyzed in this article. In addition, we reviewed data on the prevalence and the clinical management of some peculiar toxicities ibrutinib related such as lymphocytosis, major bleeding and atrial fibrillation.

Expert opinion: Ibrutinib has radically changed the scenery of relapsed/refractory CLL treatment and established an important paradigm in the molecularly targeted approach of this disease. Discontinuation of ibrutinib is rarely due to adverse events related to the drug. Patients who discontinue treatment represent a challenge to the physicians because treatment options are very limited.     

Dasabuvir: a new direct antiviral agent for the treatment of hepatitis C

Introduction: Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) has revolutionized the care of infected patients. Among these novel compounds are non-nucleoside analogs, which bind viral RNA-dependent RNA polymerase resulting in a conformational change inhibiting RNA synthesis.

Areas covered: Efficacy and tolerability of treatment regimens containing the non-nucleoside analog polymerase inhibitor dasabuvir (ABT-333).

Expert opinion: Dasabuvir-containing regimens achieve high rates of sustained virologic response in HCV genotype 1a and 1b–infected patients when combined with other DAAs, namely paritaprevir (ABT-450), ritonavir and ombitasvir (ABT-267). In the populations studied, dasabuvir seems to be well tolerated and safe. The major limitations of this novel drug are its genotype-restricted activity, the necessity to include ribavirin for HCV genotype 1a and the emergence of resistance if not combined with other DDAs.     

Low-dose SoluMatrix diclofenac: a review of safety across two Phase III studies in patients with acute and osteoarthritis pain

Introduction: Similar to other NSAIDs, diclofenac is associated with serious dose-related cardiovascular, gastrointestinal, and renal adverse events. Low-dose SoluMatrix diclofenac, containing submicron particles of diclofenac, was developed to provide effective analgesia at lower drug doses compared with currently available NSAIDs.

Areas covered: The efficacy and safety of low-dose SoluMatrix diclofenac was evaluated in two randomized, placebo-controlled Phase III studies: a study in patients with acute pain following bunionectomy surgery and a study in patients with osteoarthritis pain of the hip or knee. In this review article, we summarize safety data from these studies.

Expert opinion: The safety results from the Phase III studies indicate that all dosing regimens of low-dose SoluMatrix diclofenac up to 12 weeks are generally well tolerated. Few serious gastrointestinal, cardiovascular, renal, or hepatic adverse events commonly associated with NSAID use were reported in these studies. Although not directly compared, the safety of SoluMatrix diclofenac was similar to findings for other diclofenac drug products. The potential for safe and effective management of acute and chronic pain at reduced NSAID doses is attractive; definitive characterization of SoluMatrix diclofenac safety requires confirmation by long-term studies.     

Prasugrel hydrochloride for the treatment of acute coronary syndromes

Introduction: P2Y12 receptor antagonists, by inhibiting platelet activation and subsequent aggregation, are critical to prevent ischemic event recurrence after an acute coronary syndrome (ACS). Prasugrel is a third-generation thienopyridine whose metabolites target the P2Y12 receptor. Compared with clopidogrel, prasugrel has a more potent, faster in onset, and more consistent P2Y12 receptor inhibition.

Areas covered: This review describes prasugrel chemistry, pharmacokinetics, pharmacodynamics and clinical studies. In a Phase III randomized clopidogrel-controlled trial, prasugrel improved cardiovascular outcome (risk reduction of cardiovascular death, non-fatal heart attack and non-fatal stroke) at the cost of increased major and fatal bleeding complications. Prasugrel, in combination with aspirin, has been approved by European and American regulatory agencies for the prevention of atherothrombotic events in patients with ACS who undergo percutaneous coronary intervention (PCI).

Expert opinion: Prasugrel is effective for managing ACS patients with planned PCI and it offers an alternative with potential benefits over clopidogrel. Prasugrel is currently challenged by ticagrelor, a P2Y12 receptor antagonist with different pharmacokinetic/pharmacodynamic properties. The superiority of one drug to the other cannot be reliably estimated from the current trials. Ongoing randomized and observational studies may help to provide valuable information on the safety and efficacy of these two drugs and their respective places with ACS patients.     

Drug safety evaluation of apremilast for treating psoriatic arthritis

Introduction: Apremilast is an orally available small molecule that targets PDE4. PDE4 modulates intracellular signaling and thereby can impact various proinflammatory and anti-inflammatory mediators. Apremilast has been approved by the USA FDA for the treatment of active psoriatic arthritis (PsA) and moderate-to-severe psoriasis (PsO). Although there are several therapies approved and used for the treatment of PsA, there is still an unmet need for additional effective and well-tolerated therapeutic options. In PsA clinical trials, apremilast has been shown to be efficacious and to have an acceptable safety profile.

Areas covered: This review article covers the mechanism of action of apremilast, its efficacy in clinical trials and a detailed focus on its safety profile, mainly from Phase III clinical trials.

Expert opinion: Based on the available literature, apremilast has proven to be an efficacious therapy for PsA and PsO. It may offer some advantage as compared to other therapeutic options given its favorable safety profile, including a lack of need for routine laboratory monitoring.     

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Introduction: The evidence base for disease-modifying anti-rheumatic drugs used in psoriatic arthritis (PsA) is surprisingly weak, with most having little robust evidence to support their clinical use. Furthermore, there remain safety and tolerability concerns with both these and more recently available biological therapies. Apremilast, a novel, small molecule, represents the first oral therapy specifically developed for PsA.

Areas covered: This review describes the pharmacokinetic properties of apremilast and available data demonstrating significant benefits to both clinical and histological features of inflammatory arthritis. The key findings from a large Phase III clinical program will also be discussed, including short- and long-term efficacy outcomes and, importantly, the safety profile. Indications other than PsA will also be briefly reviewed. Given the recent nature of much of the data, published literature as well as information available only in the abstract format are included in this review.

Expert opinion: Studies show that treatment with apremilast results in significant improvement in both skin psoriasis and PsA symptoms. Apremilast has been approved by both the United States FDA and European Medicines Agency for treatment of PsA. Use of this medication is recommended in active PsA patients, according to local licensing.     

Drug safety assessment of oral formulations of ketoconazole

Introduction: Ketoconazole was the first broad-spectrum oral antifungal approved by the FDA in 1981. Post-marketing reports of drug-related hepatotoxicity, endocrine dysregulation and drug interactions resulted in market withdrawal of the drug in some countries and strict product relabeling in others.

Areas covered: This drug safety review summarizes reports of oral ketoconazole-related adverse events retrieved from a search of the PubMed database using the search strategy ‘ketoconazole OR Nizoral AND hepat*’, references from relevant publications, and data from the FDA Adverse Event Reporting System.

Expert opinion: Although oral ketoconazole is effective in treating fungal infections, the potential for drug interactions, endocrine dysregulation, and hepatotoxicity may outweigh its benefits. Newer oral antifungals have similar or greater efficacy in treating dermatologic conditions and are associated with less risk. Likewise, newer agents with specific targets and fewer drug interactions have been developed to treat systemic fungal infections. Therefore, by the time ketoconazole prescribing guidelines were amended, its use had already largely been replaced with newer antifungals. Being that ketoconazole was the first broad-spectrum oral antifungal, experience with the drug made patient safety, and especially hepatic safety, an important consideration in future antifungal development.