Drug tolerability: How much ambiguity can be tolerated? A systematic review of the assessment of tolerability in clinical studies.

AIMS: Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient-reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability. METHODS: The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability". RESULTS: Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty-five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability. CONCLUSIONS: Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient-centred healthcare.

Drug rechallenge following drug-induced liver injury.

Drug-induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3-5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high-risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high-risk drugs. CONCLUSION: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646-654).

Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies.

OBJECTIVE: Previous analysis of US FDA Medwatch safety alerts for monoclonal antibody therapeutics demonstrated that premarketing clinical trials can predict more than half of safety concerns. We expanded this analysis to assess whether the predictable alerts are detected sooner than the unpredictable alerts. METHODS: Times to alert were compared using Mann-Whitney test, Kolmogorov-Smirnov test, and using curves displaying cumulative frequencies of alerts over time. RESULTS: Until December 31, 2013 inclusive, 76 Medwatch alerts for therapeutic monoclonal antibodies were reported: 43 predictable vs. 33 unpredictable. Predictable alerts were reported at a median (IQR) of 41 (19-77) months after approval vs. 53 (23-73) months for the unpredictable alerts. The mean (SE) was 52.07 (6.69) months and 55.91 (7.06) months for the predictable and unpredictable, respectively. Although the difference of 12 months between medians of time to alert was observed, the difference was not demonstrated as significant. Cumulative frequency curves show that predictable alerts were detected sooner until month 73 after approval, when ~ 80% of alerts were detected. Immunological reactions (such as infusion reactions, anaphylaxis, and reactions due to antibodies) were identified early; all 12 such alerts were released before the curves of cumulative frequencies cross at month 73. On the other hand, reactions occurring after the curves cross are predominantly late-occurring cancers and opportunistic infections. CONCLUSIONS: The results imply that focus on predictable reactions defined as potential risks may play a role in early detection of important safety concerns.

Monoclonal Antibodies as Neurological Therapeutics.

Over the last 30 years the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysiological mechanisms, including multiple sclerosis, migraines and neuromuscular disease. In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these diseases. Untangling the molecular mechanisms of disease allows monoclonal antibodies to block disease pathways accurately and efficiently with exceptional target specificity, minimizing non-specific effects. On the other hand, accumulating experience shows that monoclonal antibodies may carry class-specific and target-associated risks. This article provides an overview of different types of monoclonal antibodies and their characteristics and reviews monoclonal antibodies currently in use or under development for neurological disease.

Intentional rechallenge: does the benefit outweigh the risk?

Rechallenge is defined as the readministration of a medication suspected of being a possible cause of an adverse reaction and which has been discontinued as result. It may be unintentional when the appearance of a reaction was initially not attributed to the medication. A rechallenge may be intentional when a prescriber decides that the benefit of rechallenge will outweigh its risk. When considering intentional rechallenge, one should take into account the benefit/risk balance of the suspected causative medication, and the benefit/risk balance of the best available alternative treatment or no treatment. Clinical knowledge is essential in benefit/risk assessment but there is currently no suitable tool to guide the decision on rechallenge. This article aims to propose points to consider in the creation of reaction-specific algorithms for risk assessment and management in the case of drug rechallenge.

Atrio-ventricular block as the first presentation of disseminated Lyme disease.

A 36 year old male patient presented to emergency cardiology department because of fatigability. ECG revealed high grade II atrio-ventricular block and bradycardia of 31 beats/min. An erythema increasing in size to up to 7-8 cm in diameter appeared a month earlier and spontaneously resolved within 10 days. ELISA testing for antibodies against Borrelia burgdorferi IgM was positive and IgG titer was 1:40. Intravenous ceftriaxone 2g qod, and 0.5 g metronidazole tid lead to regression of grade II block to grade I block within 2 days. Grade I block persisted for an additional 10 days. This is a relatively rare case of early occurrence of Lyme carditis within one month of exposure as the first sign of Lyme disease dissemination.

[Clinical trials of statins and fibrates --a meta-analysis].

INTRODUCTION: Several clinical trials of hypolipidemics showed a decrease in mortality by 30-40%, while others showed detrimental or no effects. The question remains: which trial should be the basis of clinical decision making in the choice of hypolipidemic therapy? MATERIAL AND METHODS: Meta-analysis is a method for combining research results of several studies. Effects of statins and fibrates with respect to placebo, were assessed by systematic literature review and meta-analysis. Medline and CENTRAL databases were searched using the following keywords: hyperlipoproteinemia, hypolipidemic agents and individual drug names. The main inclusion criteria were as follows: statin or fibrate, placebo controlled randomized trial, at least one year treatment on average, at least 100 patients per study arm and reported mortality. RESULTS: Fibrates showed almost complete absence of treatment effects on mortality with odds ratio of 0.99 and 95% confidence interval 0.80 - 1.11. The odds for statins were 0.87, 0.80 - 0.95. DISCUSSION: Despite the absence of treatment effects of fibrates, it is noteworthy that inclusion criteria of early fibrate trials focused mainly on cholesterol with recent identification of elevated triglycerides as an independent risk factor. As fibrates exert the most pronounced effect on triglycerides, they still may show effect in target populations. Effects of statins are confirmed, but they are noticeably lower than in individual trials which are given most publicity. CONCLUSION: Even after several decades of fibrate use, conclusive evidence of their beneficial effects still needs to be elucidated in appropriately designed trials. However, a beneficial effect of statins on mortality decrease has been proven. Meta-analysis has an important role in estimating true treatment effects and in the practice of evidence-based medicine.