Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector

Background: The anti–interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab.

Methods: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI.

Results: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns.

Conclusions: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study.

Clinical Trial Registration: NCT02678988, NCT02682823     

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate,SHR-A1403, in rodents and non-human primates

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody–drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys.

2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t_1/2) of ADC ranged from 4.6 to 11.3?days in the three species.

3. Tissue distribution study in tumor-bearing mice showed high accumulation of ¹²⁵I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug.

4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC.

5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR?=?5 to 6 and DAR?=?1, respectively, and therefore prompted selection of an appropriate DAR value (DAR?=?2) for SHR-A1403 used in preclinical development and clinical trials.

6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.     

Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.

Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.

Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.

Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.     

Routine care interventions with the parents of adult drug and alcohol users

Introduction and aims: To explore routine care interventions which enable parents to support the therapeutic effort of their adult child in drug and alcohol treatment.

Design and methods: Inductive content analysis was used to analyze the experiences of 31 Greek addiction professionals who participated in focus groups.

Findings: Professionals adopted various interventions which included (a) respond to parents quest for help, (b) involvement of the distant parent in treatment, (c) boundary setting, (d) facilitation of parent-child communication, and (e) support of parental changes. These interventions were perceived as necessary, both for motivating and sustaining the client’s change, and for alleviating the parents’ chronic grief and distress over their child’s addiction.

Conclusion: Overall, addiction professionals perceived low intensity interventions, information giving, and non- judgmental informal interactions as catalysts for the parents involvement in addiction treatment.     

Gender,subclinical organ damage and cardiovascular risk stratification in hypertensive patients

Background: The aims of the study were to assess subclinical organ damage in men and women with hypertension and its subsequent effect on cardiovascular risk, and use of new statistical methods for more precise estimation of cardiovascular risk using vascular cardiovascular risk factors: ankle–brachial index (ABI), intima–media thickness (IMT) and pulse wave velocity (PWV).

Methods: We studied 200 patients: 100 hypertensive and 100 normotensive. The parameters we evaluated included: patient age, ABI, IMT, PWV, serum uric acid and serum C-reactive protein (CRP). In addition, the cardiovascular risk according to the SCORE and Framingham scales was assessed.

Results: In the hypertensive group, there were significant correlations between ABI and the Framingham scale in both sexes. In hypertensive women, there were also significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

In normotensive women, there were significant correlations between ABI and the SCORE scale risk, and between ABI and the Framingham scale risk. In normotensive men, there were significant correlations between PWV and the SCORE scale risk, and between PWV and the Framingham scale risk. Lastly, in the group of normotensive men, there were significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

The possibility of correctly classifying a patient into the high-risk category by a logistic regression model using synchronous ABI, IMT and PWV was high – 74% for the risk according to the SCORE scale (66% in men, 88% in women), and 98% for the Framingham scale.

Conclusions: The addition of recognized subclinical target organ damage tests to the estimation of cardiovascular risk can significantly strengthen the prevention of cardiovascular disease.

Cardiovascular risk estimation follow-up with ABI, PWV and IMT increased the probability of correctly classifying people, especially women, into an at least high-risk category according to the SCORE scale, which has valuable therapeutic implications.     

A tearable dissolving microneedle system for shortening application time

Objectives: A tearable dissolving microneedle system (TD-MN system) was developed for shortening the time required to administer drugs into the skin through the dissolving microneedles.

Methods: TD-MN system consisted of an array of tearable dissolving microneedles (TD-MN) and micro-pillars. The microneedle tips had a female part to integrate with the micro-pillars. The micro-pillars exerted a vertical force to cause the separation of the tips from the base. The separation force exerted by six TD-MN arrays with different thicknesses of separation region was measured. The TD-MN system with trypan blue was inserted into porcine skin to observe the separation of the microneedle tips, and then calcein was added separately to observe drug diffusion into the skin.

Results: The thickness of the tearable region and the depth of the female part were a function of the concentration and volume of the molding solution. The separation force increased as the thickness of the tearable region increased. Nine tips were successfully separated from the base by applying a force of through the micro-pillars.

Conclusions: The TD-MN system could provide immediate administration of a drug, resulting in improved patient convenience as well as delivery of the correct drug dose.     

Lives of Substance: a mixed-method evaluation of a public information website on addiction experiences

Aims: The Lives of Substance (LoS) website presents personal experiences of drug use and ‘addiction’ in people’s own words as part of a larger project of complicating public discourses of addiction, countering stigmatising misconceptions and acting as an intervention in the social production of addiction. This article presents the findings of a mixed-method evaluation of the website, and comments on some of the methodological and practical challenges of evaluating health-related online information resources.

Method: Three data sources were used to examine such as the reach of the website (website analytics); experiences of the website audience (responses to an evaluation survey on the website); and other indicators of use and impact (including social media referrals and organisational links).

Results: In the 10-week evaluation period, 3970 unique users visited the website. Comments provided via the online survey endorsed the website as a means of challenging stereotypes and as presenting drug use as only a ‘part of a person’s whole life’. Twenty-four organisations had linked to the website and 987 social media referrals were recorded.

Conclusion: These data indicate that the LoS website is having some success as a resource for countering addiction-related stigma and offering more holistic and inclusive social understandings of addiction.     

Confidentiality and cultural competence? The realities of engaging young British Pakistanis and Bangladeshis into substance use services

Aims: This paper focuses on the reasons for the under-representation of British South Asians in substance use services. Based on a small-scale evaluation of a substance use service that delivers targeted outreach support within two predominantly Pakistani and Bangladeshi communities in the north west of England, this paper contributes to the debate around how substance use services can best engage with young British Pakistani and Bangladeshi substance users.

Methods: Semi-structured interviews (with six staff members, 18 young Pakistani and Bangladeshi service users, and 18 stakeholders and partner agencies), a detailed ethnographic observation of the service, and an analysis of routinely collected quantitative monitoring data.

Findings: The paper highlights the importance of what Fountain terms low threshold/open access services. Alongside this, the paper argues that the building of trust and confidence in a substance use service is a key when it comes to engaging with young Pakistani and Bangladeshi substance users. Yet this necessary process takes time: something that is at odds with the current trend towards short-term funding regimes and ‘quick wins’.

Conclusions: The paper concludes by advocating the need for, not only a diverse range of engagement strategies, but also a longer term approach when it comes to developing and delivering substance use services aimed at successfully engaging with this particular group of substance users.     

Safety concerns of biosimilar hormone products

Background: Currently, biotherapeutic medicines are the most effective options for the treatment of many severe and chronic diseases. For faster market entry of biotherapeutic products and their cost reduction, the principles of “biosimilarity” have been developed. Development and licensing of biosimilars is allowed only after the end of patent exclusivity of the original preparation period.

Purpose: Characteristics of the main safety parameters of biosimilar hormone preparations licensed by EMA.

Methods: This paper analyzes the results demonstrating the similarities and differences between biosimilar and reference hormone products indicated in the EPAR (public assessment report) for the examination of materials presented for the licensing of biosimilar products.

Results: During the development of biosimilar hormone medicines, differences in the glycosylation profile between biosimilar and reference preparations are revealed. As biotherapeutical preparations are produced by cells, the differences in glycosylation profile between biosimilar and referent preparation are predictable. While carrying out clinical studies, a high similarity of biosimilar and reference product effectiveness is shown, but some differences between them in the safety profile are revealed.

Conclusions: The study of biosimilar product safety has shown the necessity of further improvement in safety and standard approaches for the assessment of the immunogenicity of biosimilar products.     

Assessment of adherence to medication in patients after myocardial infarction treated with percutaneous coronary intervention. Is there a place for newself-reported questionnaires?

Introduction: Non-adherence to medication regimen after myocardial infarction (MI) leads to increased morbidity and mortality and generates additional cost to the healthcare system.

Objectives: The aim of this systematic review was to critically discuss assessment methods of adherence to medication in patients after myocardial infarction treated with percutaneous coronary intervention and the possible application of a new self-reported questionnaire.

Methods: A systematic investigation of all published literature was conducted to minimize the risk of bias. A database search (PubMed, CENTRAL and Google Scholar databases) from January 1998 through December 2017.

Results: Adequate assessment of patient adherence to treatment is necessary to understand the potential for adverse outcomes. Methods developed for adherence evaluation are classified as subjective and objective or as direct and indirect. Direct, objective measures reflect pharmacokinetics and include measurement of the drug or its metabolite concentration, evaluation of the presence of biological markers given with the drug and direct observation of patients’ medication-taking behavior. Several indirect, objective methods are based on evaluation of the availability of prescribed medications assuming that medication is taken exactly as prescribed. Assessment of the effectiveness of treatment, both at the pharmacodynamic and clinical level, indirectly but objectively reflects adherence to treatment. Subjective methods, including patient-kept diaries, patient interviews and self-reported questionnaires, due to their simplicity, real-time feedback and low cost, are often used for adherence evaluation in clinical practice.

Conclusions: In spite of the availability, convenience and variety of methods, measuring adherence still remains a real challenge. Using a well designed questionnaire provides an opportunity to identify patients at increased risk of non-adherence and the obstacles impeding implementation of the treatment plan, allowing implementation of tailored interventions in order to improve patient medication-taking behavior.     

Secondary cannabis use among London drug treatment service clients

Background: Cannabis is the second most commonly used substance after alcohol among people seeking treatment for other drug use, but no statistics are available regarding secondary cannabis use among drug treatment clients.

Objectives: To investigate levels of secondary cannabis use among drug treatment clients and perceived need for support addressing this use among clients and staff.

Methods: Cross-sectional surveys of clients (N?=?295) and staff (N?=?33) were conducted in 2015 at four London drug and alcohol treatment services. Client measures included recent drug use, type of cannabis used, Severity of Dependence Scale for cannabis, and views on secondary cannabis use treatment. Staff measures included definition of problem cannabis use, importance and timing for addressing secondary cannabis use.

Results: Among clients, 39.7% reported recent secondary cannabis use, with 30.8% of these clients meeting criteria for problem use. Problem users were more likely to be interested in receiving treatment for cannabis use than non-problem users (51.4% versus 10.8%, p?<?.001). Nearly half of staff (48.5%) thought secondary cannabis use should be addressed early in treatment.

Conclusions: Two out of five drug treatment clients used cannabis and a third experienced cannabis-related problems. Many are willing to address cannabis use, but defined treatment pathways are needed.     

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles – development,characterisation, and in vitro assessment of bioactivity for cardiac applications

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP).

Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method.

Results: Spherical MPs showed an average particle size of 2?µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15?days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit⁺ cells.

Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.     

A cross-national comparison of the Twitter feeds of popular alcohol brands in India and Australia

Aims: To evaluate (i) the types of techniques alcohol marketers utilise to facilitate user engagement with content on leading Indian and Australian Twitter alcohol brand pages and (ii) the extent to which users engage with this content in two diverse national contexts.

Methods: The 10 alcohol brands per country with the greatest Twitter presence were identified based on the number of ‘followers’. Number of tweets, photos, and videos were collected and the type of content noted for each brand between 1 January 2016 and 29 February 2016. The data were analysed via an inductive coding approach using NVivo10.

Results: In total, the brands had accumulated up to 150,386 followers (Indian: 110,032; Australian: 40,354). The techniques utilised were a mix of those that differed by country (e.g. India: sexually suggestive content versus Australia: posts related to the brand’s tradition or heritage) and generic approaches (e.g. alcohol sponsorship of sport, music, and fashion; offering consumption suggestions; organising competitions; giveaways; and use of memes).

Conclusions: The flexibility of Twitter, which complements traditional marketing, allows brands to adapt and deliver their online alcohol content in specific national contexts and to capitalise on the cultural meanings users invoke in their interactions with the brands.     

Metabolic disposition of WTX101 (bis-choline tetrathiomolybdate) in a rat model of Wilson disease

1. WTX101 (bis-choline tetrathiomolybdate) is an investigational copper (Cu)-protein-binding agent developed for the treatment of Wilson disease (WD), a rare genetic disorder caused by mutations in the ATP7B Cu-transporter and resulting in toxic Cu accumulation.

2. Mass balance of a single intravenous WTX101 dose, measured as molybdenum (Mo), was assessed over 168?h in control (Long Evans Agouti [LEA]) and Long-Evans Cinnamon (LEC) rats, a WD model.

3. In LEC rats, Mo was partially excreted (up to 45%); 29% by renal clearance, and faecal clearance, still ongoing at 168?h, accounted for 16%. In contrast, in LEA rats, Mo was almost fully excreted (～87%); 79% was renally cleared with only 7% faecal excretion.

4. In LEC rats, the proportion of faecal to renal Mo excretion was enhanced (4:6) compared to controls (1:9).

5. Substantially more Mo was found in LEC liver and kidney compared with LEA tissues, in line with tissue Cu distribution.

6. These findings are consistent with the WTX101 mechanism of action: in the WD model, excess Cu is removed from hepatic metallothionein and retained within the stable tetrathiomolybdate-Cu-albumin tripartite complex, preventing tetrathiomolybdate degradation and resulting in less urinary elimination and greater faecal excretion than in controls.     

Assessment of drug–drug interaction potential and PBPK modeling of CC-223, a potent inhibitor of the mammalian target of rapamycin kinase

1.?CC-223 was studied in vitro for metabolism and drug–drug interactions (DDI), and in clinic for interaction with ketoconazole.

2.?In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3) and imine (M13), with M1 being the most prominent metabolite.

3.?CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60–70% in healthy volunteers.

4.?CC-223 (IC₅₀?≥?27?µM) and M1 (IC₅₀?≥?46?µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes. CC-223 and M1 were moderate inducers of CYP3A in human hepatocytes.

5.?CC-223 was a substrate of BCRP, and M1 was a substrate of P-gp and BCRP. CC-223 was an inhibitor of P-gp (IC₅₀?=?3.67?µM) and BCRP (IC₅₀?=?11.7?µM), but at a clinically relevant concentration showed no inhibition of other transporters examined. M1 is a weak inhibitor of P-gp and BCRP.

6.?PBPK model of CC-223 and M1 was developed and verified using clinical results. Model based predictions of DDI with ketoconazole were in agreement with observed results enabling prospective predictions of DDIs between CC-223 and CYP3A4 inhibitors.     

Examining the blurred boundaries between medical and recreational cannabis – results from an international study of small-scale cannabis cultivators

Aim: To compare characteristics of recreational vs. medical growers in a sample of small-scale cannabis cultivators from 12 countries.

Methods: Six thousand eight hundred ninety six respondents who took part in an online survey were divided into three groups as: those who reported growing for recreational use, those cultivating for medical purposes who also reported use of other illegal drugs, and those who reported cultivation for medical use and didn’t use other illegal substances. The groups were compared using multinomial logistic regression.

Findings: In comparison to recreational growers, the two groups of medical growers included more females, consumed cannabis more frequently, and were more likely to cite health-related motivations for growing. The medical growers without other illicit drug use shared some of the same features with the medical growers with illicit drug use, but in comparison to both other groups, they were older, used less alcohol and tobacco, and were less likely to be involved in illicit activities other than drug crimes.

Conclusions: Findings suggest that claims of medical use are not simply an attempt to justify personal cannabis consumption, but do at least partly reflect a genuine belief in medical benefit. However, those growing cannabis for medical reasons form a heterogeneous group of people.     

Extended-release morphine sulfate and naltrexone hydrochloride (EMBEDA): naltrexone-associated withdrawal and abuse-related effects in patients with chronic pain and recreational opioid users

Objective: To review the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across EMBEDA (MSN; extended-release morphine sulfate with sequestered naltrexone) studies.

Methods: Five studies in pain patients and a safety review summarizing AE reports during the first year following approval of MSN were assessed for withdrawal reports. Three of these studies also assessed Clinical Opiate Withdrawal Scale (COWS) scores. Plasma naltrexone concentrations of MSN-treated individuals were summarized. Abuse potential was assessed in four studies in non-dependent recreational opioid users.

Results: Withdrawal AEs occurred in 13/1781 patients across five MSN studies, and 25/182 cases involving withdrawal were reported in the safety review. In three of these studies, 11/964 patients experienced moderate withdrawal (COWS score?=?13–24) and 1/964 patients experienced moderately severe withdrawal (score?=?28); all were either non-compliant with study drug, had undetectable plasma naltrexone concentrations, or were tapering to placebo. In ≥89% of plasma naltrexone concentration samples from patients who took MSN (n?=?166), naltrexone was below the limit of quantification (4.0?pg/mL). In four studies with non-dependent recreational opioid users (n?=?118), crushed MSN was associated with significantly lower scores of drug liking, high, and take drug again than crushed morphine sulfate (p?≤?0.005).

Conclusions: When taken intact as directed, naltrexone in MSN does not precipitate withdrawal. However, when MSN is crushed, naltrexone mitigates, but does not eliminate, the euphorigenic effects of crushed morphine sulfate.