Clinical safety and tolerability of tedizolid phosphate in the treatment of acute bacterial skin and skin structure infections

Background: We evaluated safety and tolerability of tedizolid phosphate at the 200-mg once-daily dose approved for 6-day treatment of skin and skin-structure infections.

Research design and methods: Clinical adverse event (AE) and laboratory data were pooled across completed clinical studies (13 phase 1, two phase 2, and two phase 3), for all participants who received ≥1 dose of tedizolid 200 mg, linezolid 600 mg (phase 3 only), or placebo (phase 1 only).

Results: 1280 participants received tedizolid (phase 1: n = 355; phase 2/3: n = 925). In total, 13% received >6 doses of tedizolid (range: 7–21); in phase 2/3, 94% of participants received ≥5 doses (range: 5–10). Drug-related AEs occurred in 27% of participants (most commonly gastrointestinal reactions in 13% of participants and headache in 4%). Most AEs were mild-moderate in severity; <1% of participants discontinued treatment due to AEs. Tedizolid and linezolid had similar frequency, severity, and types of drug-related AEs. Tolerability in clinically important subpopulations (obese, n = 346; elderly, n = 99; renal impairment, n = 40; hepatic disease/impairment, n = 294) appeared comparable to the overall population.

Conclusions: Tedizolid, given orally or intravenously at 200 mg, has a favorable safety profile. Clinical trial and postmarketing experience with treatment ≥7 days is limited.     

Anti-inflammatory agents to treat or prevent type 2 diabetes,metabolic syndrome and cardiovascular disease

Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD.

Area covered: The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists.

Expert opinion: The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.     

Comparative usability study for a certolizumab pegol autoinjection device in patients with rheumatoid arthritis

Objectives: To compare the usability of a new certolizumab pegol (CZP) autoinjector with the adalimumab, etanercept, and golimumab devices in patients with rheumatoid arthritis.

Methods: Two identical studies were performed in 2013 and 2016; patients performed a simulated self-injection with the CZP autoinjector and the most up-to-date device versions at the time in a randomized, consecutive sequence. The primary end point was the ranking of the four autoinjectors in order of preference. Device usability and intuitiveness were assessed across a range of secondary and exploratory end points.

Results: The 2013 and 2016 study populations included 76 patients each; a significant majority (2013: 67%; 2016: 59%) ranked the CZP autoinjector as their most preferred device (p < 0.001). Most patients agreed that the CZP autoinjector was easier to use, start, and manipulate, and were more willing to use it than the comparator devices (p < 0.001 for all pairwise comparisons with CZP). Likert score differences also favored the CZP autoinjector regarding how easy it was to determine injection completion. The CZP autoinjector was associated with a low rate of use error.

Conclusions: In both studies, the CZP autoinjector was the preferred choice compared to the alternative devices and was associated with a high level of patient satisfaction.     

Multiple sclerosis as an adverse drug reaction: clues from the FDA Adverse Event Reporting System

Background: Possible relationship between drug exposure and multiple sclerosis (MS) development is insufficiently investigated, and further challenged by the incomplete understanding of MS etiopathogenesis. The study aims to investigate whether drug exposure could contribute to MS, by analyzing worldwide spontaneous reporting archives of adverse drug reaction (ADRs).

Research design and methods: We retrieved information from the US Food and Drug Administration Adverse Event Reporting System (FAERS) over a 13-year period. Reporting odds ratio (ROR) for MS was calculated for each single substance. Disproportionality signals were considered when at least 10 cases were retrieved with a lower limit of the 95% confidence interval (CI) >1.

Results: After a customized data-mining process, 3,226 reports of MS were retrieved. ‘Antineoplastic and immunomodulating drugs’ (33% of total reports) were the most frequently reported, with 10 disproportionality signals, including etanercept (445 cases; ROR: 2.48; 95% Cl: 2.24–2.74), adalimumab (329; 2.05; 1.83–2.30), and infliximab (119; 2.25; 1.87–2.70). We also observed signals for drugs acting on hormone balance, bone density, and central nervous system.

Conclusion: Our findings suggest that immunomodulatory drugs increase the risk of MS and point out that some other drug classes should be further investigated for this risk.     

An overview of developing TNF-α targeted therapy for the treatment of psoriasis

Introduction: Three biologic drugs targeting TNF-α are approved to treat moderate-to-severe cutaneous psoriasis. These are adalimumab, etanercept and infliximab. These drugs are given by subcutaneous injection or intravenous infusion, and while generally safe and effective, they are expensive with potential for side effects. Thus, numerous new drug candidates are under development that also target TNF-α.

Areas covered: In this review, the authors detail several drugs under development that target TNF-α, focusing on those drugs in preclinical, Phase I and II trials. The authors describe emerging biologic psoriasis therapies, including biosimilars and novel biologics, in addition to several synthetic and naturally derived small-molecule drug candidates.

Expert opinion: The currently approved TNF-α antagonists benefit from over 10 years of safety and efficacy data. The expense and method of administration of these biologics, however, can be cumbersome, and less expensive alternatives have the potential to benefit patients with psoriasis. It is inevitable, despite the introduction of new anti-IL-17 therapies, that established TNF-α targeted therapies, as well as newcomers targeting TNF-α, will continue to play an important role in the lifelong management of psoriasis.     

Frequency and characteristics of infusion reactions during biosimilar infliximab treatment in inflammatory bowel diseases: results from Central European nationwide cohort

Background: Safety data of the ‘real life’ use of an infliximab biosimilar, CT-P13 in inflammatory bowel disease (IBD) are still lacking. Our aim was to assess the frequency and characteristics of infusion reactions during CT-P13 therapy in 13 Hungarian and 1 Czech IBD centres.

Methods: Clinical and safety data was registered at fixed appointments. Trough levels and anti-drug antibody (ADA) concentration were measured by ELISA. Association between demographic, clinical, laboratory parameters and infusion reaction rates were evaluated statistically.

Results: Three hundred and eighty-four IBD patients were included. Twenty-eight Hungarian IBD patients (9.6%) developed infusion reaction during the treatment, 64.3% of them was previously exposed to anti TNF therapy. No infusion reaction occurred in the Czech population. CT-P13 therapy had to be stopped in 17 patients who developed infusion reaction and was switched to adalimumab in 12 patients. However in 39.3% of patients developing infusion reaction CT-P13 therapy was continued with the use of premedication. Cumulative ADA positivity rates were 8.7%, 19.3%, and 28.0% at weeks 0, 14, and 30. Previous anti-TNF-alpha exposure (30% vs. 3.1%, p < 0.001, OR 6.3 (2.7–14.6)) and ADA positivity (32.6% vs. 4.1%, p < 0.001, OR 19(5–73)) during the induction therapy were predictive factors for infusion reactions.

Conclusions: Patients with previous exposure to anti-TNF-alpha and ADA positivity during the induction therapy were more likely to develop infusion reactions.     

First line of biological drugs in rheumatoid arthritis: a medication persistence analysis

Objectives: To evaluate the persistence of biological drugs used as the first line of biological treatment in patients diagnosed with rheumatoid arthritis. The predictors associated with persistence have also been verified.

Methods: We evaluated a historical cohort composed of users of the Brazilian National Health System in the period between 2006 January and 2014 December. The endpoint was the medication persistence at 12 months.

Results: A population composed of 66,787 individuals started the first line of biological drug. Out of such individuals, 34,595 (51.80%) persisted in the treatment at 12 months. Abatacept was the drug that presented higher persistence, followed by golimumab, tocilizumab, etanercept, and adalimumab and, with lower persistence certolizumab and infliximab. Younger individuals, living in regions with higher social inequality by Gini coefficient, using certolizumab and infliximab in comparison with adalimumab presented a higher risk of non-persistence to treatment. Individuals from the Southeastern region were more persistent than Northeastern, Central-western, Northern and Southern regions.

Conclusion: The medication persistence was different between biological drugs. The rigorous follow-up of patients, by a multidisciplinary team, is important to enable the development of strategies for the adequate use of such drugs.     

Psoriasis during angiotensin receptor blocker exposure: an underestimated adverse drug reaction

Background: Angiotensin receptor blockers (ARBs) can induce or exacerbate psoriasis. Psoriasis is unlisted in the Summary of Product Characteristics (SmPC) of ARBs. We aimed to investigate the association between psoriasis and ARB exposure.

Methods: We reviewed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD). The association between psoriasis and ARB exposure was assessed using the case/non-case method. We also analyzed literature reports.

Results: We identified 89 reports of psoriasis during ARB exposure in the FPVD. Time to onset was most often less than 1 year. Outcome was favorable in 67% of reports after ARB discontinuation. Almost all ARBs were concerned. The reporting odds ratio (ROR) for psoriasis with this therapeutic class was 4.86 (95%CI 3.92–6.03). In the literature, we found 14 published reports of psoriasis with ARB exposure. Time to onset ranged from 6 weeks to 9 months. Outcome was also favorable after ARB discontinuation in the literature.

Conclusions: This underestimated adverse drug reaction is a class effect, time to onset is most often less than 1 year and outcome seems favorable after ARB discontinuation. The case/non-case approach highlights a potential safety signal. The SmPC of ARBs should be updated, increased awareness among healthcare professionals is warranted.     

Comparison of post-marketing surveillance approaches regarding infections related to tumor necrosis factor inhibitors (TNFi’s) used in treatment of autoimmune diseases

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi’s).

Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using Evidex^TM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss’s kappa and Cohen’s kappa (κ) were calculated to determine agreement across all three sources and between each two sources.

Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss’ kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM.

Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.     

Dose adjustment of metformin and dipeptidyl-peptidase IV inhibitors in diabetic patients with renal dysfunction

Objectives: This analysis of real-world data aimed to (a) determine the proportion of Type II diabetes (T2DM) patients treated with metformin or dipeptidyl peptidase-4 inhibitors (DPP-4i) that require dose adjustment or therapy discontinuation due to chronic kidney disease (CKD), and (b) to assess the time required to dose adjustment from the time of worsening of CKD.

Methods: In this retrospective study, two study populations were defined in a large healthcare organization. In the cross-sectional analysis, the distribution of CKD stages and the appropriate dosage of metformin and DPP-4i in 2013 was examined according to renal function among T2DM patients. In the longitudinal analysis, a cohort was defined to assess the time elapsed from first indication worsening of CKD to dose adjustment, among patients treated with those medications during years 2006–2013.

Results: Among patients treated with metformin or DPP-4i, one third of patients with CKD failed to adjust the dosage or to discontinue metformin or DPP-4i as indicated. Median time for dose adjustment or discontinuation was significantly longer for DPP-4i than for metformin (9.8 compared to 16.8 months for metformin and DPP-4i, respectively; p-value <.001).

Conclusions: This real-world data analysis showed that adjustment of dose or discontinuation of metformin or DPP-4i in patients with worsening CKD occurred less often in DPP-4i users than metformin users and took a longer time.     

Early investigational TNF receptor antagonists for the treatment of ulcerative colitis

Introduction: Ulcerative colitis (UC) is a life-long, immunologically mediated condition that results from an inappropriate activation of the mucosal immune system by intestinal luminal antigens in genetically susceptible individuals. TNF-α is a pro-inflammatory cytokine central to UC pathogenesis.

Areas covered: This review examines the evidence for the use of the anti-TNF (αTNF) medications infliximab, adalimumab, certolizumab and golimumab in the management of UC. It highlights the newer biosimilar agents that are becoming available and the early stage investigation of an orally administered αTNF agent.

Expert opinion: αTNF therapy is effective but only in a proportion of UC patients. As there is now strong evidence that UC is not just a single disease but a series of phenotypes with distinct genetic, serological and environmental aspects, understanding the heterogeneity of the innate immunological response in UC could allow for better targeted patient management. Identifying differences in the efficacy of the various αTNF agents is difficult as there are no head-to-head studies, but only infliximab has proven clinical efficacy in the management of acute severe colitis. Biosimilars to the αTNF agents are now available and with the added competition, medications costs should fall allowing for greater patient access.     

The safety of available treatments options for neuroendocrine tumors

Introduction: Neuroendocrine neoplasms (NEN) represent a heterogeneous group of malignancies generally characterized by low proliferation and indolent course. However, about half of the newly diagnosed cases are metastatic and require long-term systemic therapies.

Areas covered: This review revises the literature to summarize the current knowledge upon safety of all systemic treatment options available. Thirty three different clinical studies have been considered, including 4 on somatostatin analogues (SSA), 5 on targeted therapies, 10 on peptide receptor radionuclide therapy (PRRT), and 14 on chemotherapy.

Expert opinion: SSA are safe and well tolerated without any relevant severe adverse event and very low treatment discontinuation rate. Targeted therapies show a satisfying safety profile. Most adverse events are grade 1–2 and easy manageable with dose reduction or temporary interruption. PRRT is manageable and safe with a low rate of grade 3–4 adverse events. However, severe renal and hematologic toxicity may occur. Chemotherapy is usually considered after previous therapeutic lines. Therefore, these subjects are more susceptible to experience adverse events due to cumulative toxicities or poor performance status.

The available systemic treatment options are generally well tolerated and suitable for long-term administration. Cumulative toxicity should be taken in account for the definition of therapeutic sequence.     

Primary and secondary nonresponse to infliximab: mechanisms and countermeasures

Introduction: Primary and secondary non-response to infliximab are common in patients with inflammatory bowel disease and remain a management challenge in clinical practice.

Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease. Data on proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm for evaluation and management of non-response to infliximab is provided. Preventative measures are also discussed. Relevant articles were identified after a literature search using PubMed. Search terms included ‘infliximab’, ‘loss of response’, ‘immunogenicity’, and ‘drug monitoring’. References of identified articles were also reviewed to identify additional references.

Expert opinion: A common cause for primary and secondary non-response include inadequate dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-drug antibody levels. Therapeutic drug monitoring should be done in patients losing response to infliximab. Use of drug monitoring proactively is still under debate.     

A randomized,double-blind,single-dose,two-arm,parallel study comparing pharmacokinetics,immunogenicity and tolerability of branded adalimumab and its biosimilar LBAL in healthy male volunteers

Objectives: This study aimed to compare the pharmacokinetics (PK), immunogenicity, and tolerability of LBAL, a biosimilar of adalimumab, with the originator, Humira®, in healthy volunteers.

Methods: A randomized, double-blind, single-dose, two-arm, parallel-group study was conducted in 116 healthy subjects. They randomly received a single subcutaneous (SC) 40 mg injection of LBAL or Humira. Blood samples were collected for PK and immunogenicity assessment. PK parameters were determined using the noncompartmental method, and primary endpoint parameters were compared using the point estimates and 90% confidence intervals (CIs) of the geometric mean ratios (GMRs). Tolerability was also evaluated.

Results: The PK characteristics of the test and reference drugs were comparable. The GMR (90% CIs) for C_max and AUC_inf of LBAL to Humira were 1.01 (0.92–1.11) and 0.96 (0.83–1.10), respectively, which were within the conventional bioequivalence criteria of 0.80–1.25. No significant differences occurred in the frequency of subjects with anti-adalimumab antibody-positive responses between both drugs. Tolerability profiles including adverse events were also comparable.

Conclusion: The PK characteristics of the biosimilar LBAL and the originator Humira were similar. LBAL and Humira did not show significant differences in immunogenicity and both were well tolerated after a single SC injection.     

Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review

Introduction: Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient.

Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity.

Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.     

The pharmacokinetics,pharmacodynamics, and clinical role of fixed dose combination of tenofovir disoproxil fumarate,lamivudine and reduced dose efavirenz (TLE-400) in treating HIV-1 infection

Introduction: Co-formulated fixed dose combination (FDC) of antiretroviral drugs tenofovir disoproxil fumarate, lamivudine, and reduced dose efavirenz [TDF 300 mg/3TC 300mg/EFV400 mg (TLE-400)] is a single daily tablet recently approved for the treatment of HIV-1 infection.

Areas covered: An overview of the pharmacokinetics, pharmacodynamics and role of TLE-400 in the treatment of HIV-1 infection based on the publications from Medline and Pubmed as of February, 2018.

Expert opinion: Although TLE-400 has not been formally evaluated in a clinical trial as a new formulation, previous studies have evaluated its components individually and in different doses as other FDCs have shown favorable efficacy and safety results to support continuing its approval and indication in the management of HIV-1 infection. Due to the lower dose of EFV, TLE-400 has a lower rate of toxicity and higher tolerability compared to its predecessor, the TLE-600, which contained a higher 600 mg dose of EFV. Given its low cost and ease of administration, TLE-400 is a promising alternative first line FDC in the management of HIV-1.     

The safety of biological pharmacotherapy for the treatment of ulcerative colitis

Introduction: Biological agents are effective in ulcerative colitis (UC). Currently, 3 anti-TNF agents (infliximab, adalimumab, and golimumab) and 1 anti-integrin agent (vedolizumab) are approved for the treatment of UC. The mechanism of action of biologic agents can also give rise to several side effects, some even serious. It remains uncertain to what extent biologic treatments may be associated with an increased rate of infections, malignancies and other adverse events

Areas covered: Our aim is to review the relevant data available in the literature and briefly summarize the safety profile of biological therapy in UC. We performed a literature search using the OVID, MEDLINE, PUBMED and EMBASE databases. Also other relevant sources of safety data were also used.

Expert opinion: All biological agents currently used in UC are relatively safe. Accurate prevention measures and screening prior to start such therapies, and regular surveillance programs are strongly recommend to minimize any risk of infections, malignancy and other adverse events related to the use of monoclonal antibodies in UC patients.     

Comparison of glycemic variability in Japanese patients with type 1 diabetes receiving insulin degludec versus insulin detemir using continuous glucose monitoring: a randomized,cross-over,pilot study

Objective: To use continuous glucose monitoring (CGM) to compare glycemic variability in patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) versus insulin detemir (IDet).

Methods: Ten patients with T1D were randomly assigned to receive once-daily IDeg, followed by twice-daily IDet, or vice versa. Glucose variability was evaluated by CGM after >4 weeks of the first insulin and again after crossover to the second insulin.

Results: The total daily insulin dose (U/kg/day) and the total daily basal insulin dose (U/kg/day) were significantly lower during treatment with IDeg than with IDet [median (interquartile range): 0.55 (0.54–0.73) vs. 0.64 (0.54–0.83); P = 0.028, 0.24 (0.19–0.36) vs. 0.30 (0.19–0.39); P = 0.027]. The 24-hour mean glucose levels were not significantly different. However, their standard deviation (SD) was significantly smaller during treatments with IDeg than those with IDet [59.5 (39.5–71.0) vs. 72.8 (61.8–92.8); P = 0.008]. Their mean fasting glucose levels and the mean postprandial peak levels after breakfast and after dinner were significantly lower with IDeg.

Conclusions: A CGM-based comparison demonstrated that once-daily IDeg showed fewer glycemic fluctuations than twice-daily IDet. IDeg appears to stabilize blood glucose levels better during both daytime and nighttime (particularly, before and after breakfast) with a lower insulin dosage.