Characterising QT interval prolongation in early clinical development: a case study with methadone

Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modelling can be used to assess the probability of QTc interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate non-clinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of prodromic drug effects in humans. ECG and drug concentration data from safety pharmacology study in dogs were analysed using nonlinear mixed effects modelling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration vs. time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QTc interval of ≥ 5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans. However, an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals the drug-specific parameter in dogs. In addition, our analysis show that understanding of interspecies differences in drug disposition is required to accurately predict the QT prolonging effects in humans. Extrapolation of the effects of parent compound may not be sufficient to describe the increase in QT interval observed after administration of methadone in humans. Assessment of the contribution of enantioselective metabolism and active metabolites is critical

Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients

Bespiegelingen over Farmacologie = Reflections on Pharmacology

Ter gelegenheid van zijn afscheid als hoogleraar in de Farmacologie aan de Universiteit Leiden op vrijdag 31 maart 2017Pharmacolog

Pharmacotherapy in paediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically-based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in paediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert Opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modelling and simulation concepts to prevent further delays in the development of personalised treatments for paediatric patients

Disease Systems Analysis of Bone Mineral Density and Bone Turnover Markers in Response to Alendronate, Placebo, and Washout in Postmenopausal Women

A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n=1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism-based disease systems model to data from various treatments for osteoporosis

Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.

BACKGROUND AND PURPOSE The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. EXPERIMENTAL APPROACH Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥ 10 ms increase in QT was derived as measure of the pro-arrhythmic effect. KEY RESULTS For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥ 10 ms (Cp50) varied from 20.3 to 6.4 and 2.6 μM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 μM vs 2.0 μM for monkeys and humans, respectively. CONCLUSIONS AND IMPLICATIONS Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans

Community Isolation Project

Introduction The authors of this summary are nursing students at Seattle Pacific University, and the project goal is focused on understanding feelings of isolation in elderly communities and whether fostering social activities, such as Bingo, would improve social interaction between residents in this community. For the past two years, the COVID-19 pandemic has altered various aspects of social interaction. From masking to social distancing, societal norms and expectations evolved in a manner that promoted isolation and minimal interaction to inhibit the spread of Covid infection between individuals. Of the general populace, the most vulnerable and at risk for infection are the elderly and those with comorbidities. Subsequently, older individuals are more at risk for rigid social isolation precautions due to the risk of infection, affecting many of the individuals in this group who live in community settings such as nursing homes and long-term care facilities. This project ultimately seeks to understand how older individuals might feel after participating in community activities with one another as well as assess for any feelings of depression and social isolation post pandemic.  Background The population worked with is a subsidized living community for individuals over the age of 62. The 200-plus unit apartment complex is located in North Seattle just off the Aurora business district. Social isolation and loneliness in older adults living in communities such as this is a growing concern especially since the pandemic showing upwards of 29% of the elderly population to report being lonely in the U.S. (Taylor, et al., 2018). Although it is hard to precisely measure social isolation and loneliness, the evidence that does exist shows there is an increased risk for dementia alone, by fifty percent, with links to an increase in cardiovascular disease, stroke, anxiety, depression, and suicide (CDC, 2021). More recent studies in populations of older adults residing in senior housing communities seem to experience higher levels of loneliness due to lower-income, being alone due to the death of a spouse/partner, having fewer confiding relationships, depression, and other significant comorbidities as mentioned, as compared to those living in conventional housing (Taylor, et al., 2018). This is attributed to having less contact with family and friends, social anxiety of meeting neighbors, and altogether feeling of not being supported (Taylor, et al., 2018). The COVID-19 pandemic added more barriers to social isolation and loneliness for the elderly due to early restrictions of in-person gatherings, recreational activities within the community, family gatherings being canceled, spiritual congregations canceled, and many deaths within the community, all adding to the sense of isolation, loneliness, and depression (Webb and Chen, 2021). As far as interventions to combat loneliness and social isolation, there have been many. It is difficult to analyze due to individual experience surrounding the issues (Fakoya et al., 2020). There is not a “one-size-fits all” standardization to address social isolation and loneliness in the elderly, showing that tailoring interventions to specific community and individual needs as being the best approach (Fakoya et al., 2020). Activities with Rationale When discussing what activities or events the project should center around, the team collaborated with the property manager at the senior living community to ensure the provided activity would be both fun and engaging for the residents, as well as beneficial and information-producing for our project and the property manager. After it was determined the project would center around targeting loneliness in elderly communities, an idea was landed on creating an event that would demonstrate the importance of connection and combat isolation. A transtheoretical model of change was used as the basis for this project. This change model states that behavior change takes place through the following stages: precontemplation, contemplation, preparation, action, maintenance, and termination. To measure this, pre- and post- surveys were filled out by residents to gather data to support the health promotion project’s claims. The project at the community included two Bingo days. The specific activity was determined through popular request by the residents who had mentioned playing and enjoying Bingo as a community in the past. A week prior to the first event, pre surveys were distributed asking the residents about their experience of isolation and/or loneliness if they had any. Residents were incentivized to attend the Bingo events with promised coffee, snacks, and small prizes for Bingo winners. Residents were even given a chance to be entered into a randomized drawing for a fifteen-dollar gift card to Sprouts, a local grocery store, which was conducted at the end of each Bingo day. After the events, those who participated in Bingo were then further encouraged to fill out post surveys. These surveys questioned how it felt to engage in the community and if their feelings or loneliness/isolation had changed in order to assess the impact the bingo event had on mood and affect. For the purposes of this project, it was important not only to gather information, but to model what having community events, such as Bingo, could look like and how they would positively impact the community. Outcomes To gain a better understanding of how the community felt regarding loneliness, isolation, and their willingness to participate in group activities, pre- and post-bingo surveys were provided utilizing the Likert scale. In return, 30 pre-surveys were returned from the community. Following the event, 30 post-surveys were filled out by the residents who participated in Bingo. After reviewing the results of the pre-surveys, it was concluded that the overall community often feels a sense of loneliness, but they have an ardent desire to participate in group activities. After 2 days of Bingo, residents who joined us were asked to fill out a post-survey to gauge if the group activity had any effect on them. In almost every single post activity survey received, residents answered that playing Bingo with their community positively impacted their mental health, they would play Bingo or attend another event again, and they found it easier to build relationships with their community members while engaging in Bingo together. The community engagement surveys revealed that group activities such as bingo led to an outcome of decreased loneliness and isolation. According to the data collected, hosting and facilitating social events, specifically for older adult populations, post pandemic, is extremely beneficial to mental health and overall wellness. Conclusion Although Covid has been around for two years now, it has proven to be very difficult to navigate, especially in community settings such as this subsidized living community. This pandemic has been exceptionally problematic as facilities search for a balance betweenl encouraging social activity, and also promoting physical safety from Covid-19. While preventing the spread of the virus is certainly a priority, mental health, arguably, is just as crucial to one\u27s well-being as their physical health. The surveys collected in this project revealed that while many individuals had a strong urge to engage in social activities, a sense of loneliness in the community still exists for many people. As mentioned in other studies, there’s no “correct” way to decrease feelings of isolation as the process of overcoming this sense of remoteness may be very specific to the community. Luckily, the staff at this site are very in tune with their population and they disclosed that Bingo is a popular activity among the residents. It was important that the activity was appropriate and engaging for people of all different backgrounds as the intent of the project was to foster community engagement and improve social interactions among the group. Overall, there was a great turnout of people at both the first and second Bingo events, further exemplifying the enthusiasm many individuals shared about wanting to be more engaged in the community. Because there was such a big turnout, the group had a few challenges to overcome. Firstly, accessibility and navigation within the conference room was a little tight the first time around which the group was able to overcome by rearranging tables to accommodate for walkers and wheelchairs. Secondly, while there was a provided space and Bingo set, the budget for prizes and snacks was also very limited which led to the group contributing personal funds to the project. Lastly, while the post-surveys offered great insight, they provided information on a very small percentage of the population. The results of the surveys are from the perspective of individuals who most likely often attend group activities, which ultimately skews the information as this may not accurately represent the entirety of the population at this senior community. For a more accurate representation of the community, there would need to be a larger sample number. The project proved to be successful as many of the residents answered in their post-surveys that the Bingo event decreased feelings of loneliness and isolation, therefore positively impacting their mental health. Many of the individuals also stated in their questionnaires that they would attend more Bingo events in the future. In addition, residents were also eager to suggest other fun group activities such as painting, gardening, picnics, and dances. Moving forward, it would be beneficial for future groups to try other activities in addition to Bingo. Different events may motivate social interaction from the individuals who don’t enjoy activities such as Bingo and would facilitate a feeling of excitement in anticipation for a communal gathering that is both entertaining and interactive. This health promotion project found Bingo to be a successful event in which participants were able to maintain a safe social distance, and engage together in a fun, community activity. References Fakoya, O., McCorry, N., & Donnelly, M. (2020). Loneliness and social isolation for older adults: A scoping review of reviews. BMC Public Health, 20(129). https://doi.org/10.1186/s12889-020-8251-6 Centers for Disease Control and Prevention (2021). Loneliness and social isolation linked to serious health conditions. (n.d.).  https://www.cdc.gov/aging/publications/features/lonely-older-adults.html#:~:text=A%20report%20from%20the%20National,considered%20to%20be%20socially%20isolated Taylor, H., Wang, Y., & Morrow-Howell, N. (2018). Loneliness in senior housing communities. Journal of Gerontological Social Work, 61(6), 623-639. https://doi.org/10.1080/01634372.2018.1478352 Webb, L., & Chen, C. (2021). The covid-19 pandemic\u27s impact on older adults\u27 mental health: Contributing factors, coping strategies, and opportunities for improvement. Int J Geriatr Psychiatry. https://doi.org:10.1002/gps.564

Cost-effectiveness of ovarian stimulation agents for IUI in couples with unexplained subfertility

Acknowledgements The authors wish to thank M.P. Diamond, R.S. Legro, K. Peeraer, M. Erdem, T. Dankert, and R. Ecochard, on behalf of the IUI IPDMA collaboration, for providing data from their RCTs for the IPDMA of which the results are used in a sensitivity analysis. Funding This work was supported by ZonMw Doelmatigheidsonderzoek, grant 80-85200-98-91072. The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548).Peer reviewedPublisher PD

Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm

AIM: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain, and discuss the prerequisites and opportunities to reduce attrition and high failure rate in the development of analgesic drugs. MEHTODS: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on 1) disease mechanisms leading to chronic/neuropathic pain and 2) drugable targets which are currently under evaluation in drug development. Attention was also given to biomarkers and pharmacokinetic-pharmacodynamic modelling. RESULTS: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti- inflammatory drugs (NSAIDs). CONCLUSION: A paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than to clinical symptoms. Biomarkers need to be identified that enable characterisation of drug binding and target activity, providing the basis for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate characterisation of target engagement, and prediction of treatment effects before embarking into large clinical trials