Therapeutic drug monitoring to personalize dosing of imatinib, sunitinib, and pazopanib:A mixed methods study on barriers and facilitators

Background:Personalized dosing based on measurement of individual drug levels and adjusting the dose accordingly can improve efficacy and decrease unnecessary toxicity of oncological treatment. For imatinib, sunitinib, and pazopanib, this therapeutic drug monitoring (TDM)-guided dosing is, however, not routinely used, despite accumulating evidence favoring individualized dosing. Therefore, we aimed to identify and quantify (potential) barriers and facilitators in TDM-guided dosing for imatinib, sunitinib, and pazopanib. Methods: We performed a mixed methods study among all stakeholders involved: patients, healthcare professionals (HCPs), pharmaceutical companies, and health insurance companies. During the first qualitative part of this study, we performed semi-structured individual interviews and one focus group interview to identify all (potential) barriers and facilitators, and during the second quantitative part of this study, we used a web-based survey to quantify these findings. The interviews addressed the six domains of the implementation of change model of Grol and Wensing: (1) the innovation itself; (2) the HCP; (3) the patient; (4) social context; (5) organizational context; and (6) finances, law, and governance. Results: In the qualitative study, we interviewed 20 patients, 18 HCPs and 10 representatives of pharmaceutical and health insurance companies and identified 72 barriers and 90 facilitators. In the quantitative study, the survey was responded by 66 HCPs and 58 patients. Important barriers were on the domain of the HCP, such as a lack of experience with TDM (36.4%), on the domain of the patient, such as lack of awareness of TDM (39.7%), and the processing time for measurement and interpretation of the TDM result (40.9%) (organizational domain). Important facilitators were education of HCPs (95.5%), education of patients (87.9%) and facilitating an overview of when and where TDM measurements are being performed (86.4%). Conclusion: We identified and quantified important barriers and facilitators for the implementation of TDM-guided dosing for imatinib, sunitinib, and pazopanib. Based on our results, the implementation strategy should mainly focus on educating both HCPs and patients and on the organizational aspect of TDM.</p

Imatinib, sunitinib and pazopanib:From flat-fixed dosing towards a pharmacokinetically guided personalized dose

Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib

How Art Therapists Observe Mental Health Using Formal Elements in Art Products: Structure and Variation as Indicators for Balance and Adaptability

In clinical practice, formal elements of art products are regularly used in art therapy observation to obtain insight into clients’ mental health and provide directions for further treatment. Due to the diversity of formal elements used in existing studies and the inconsistency in the interpretation, it is unclear which formal elements contribute to insight into clients’ mental health. In this qualitative study using Constructivist Grounded Theory, eight art therapists were interviewed in-depth to identify which formal elements they observe, how they describe mental health and how they associate formal elements with mental health. Findings of this study show that art therapists in this study observe the combination of movement, dynamic, contour and repetition (i.e., primary formal elements) with mixture of color, figuration and color saturation (i.e., secondary formal elements). Primary and secondary elements interacting together construct the structure and variation of the art product. Art therapists rarely interpret these formal elements in terms of symptoms or diagnosis. Instead, they use concepts such as balance and adaptability (i.e., self-management, openness, flexibility, and creativity). They associate balance, specifically being out of balance, with the severity of the clients’ problem and adaptability with clients’ strengths and resources. In the conclusion of the article we discuss the findings’ implications for practice and further research

Sequential dependency for affective appraisal of food images

Abstract How we perceive the world is not solely determined by our experiences at a given moment in time, but also by what we have experienced in our immediate past. Here, we investigated whether such sequential effects influence the affective appraisal of food images. Participants from 16 different countries (N = 1278) watched a randomly presented sequence of 60 different food images and reported their affective appraisal of each image in terms of valence and arousal. For both measures, we conducted an inter-trial analysis, based on whether the rating on the preceding trial(s) was low or high. The analyses showed that valence and arousal ratings for a given food image are both assimilated towards the ratings on the previous trial (i.e., a positive serial dependence). For a given trial, the arousal rating depends on the arousal ratings up to three trials back. For valence, we observed a positive dependence for the immediately preceding trial only, while a negative (repulsive) dependence was present up to four trials back. These inter-trial effects were larger for males than for females, but independent of the participants’ BMI, age, and cultural background. The results of this exploratory study may be relevant for the design of websites of food delivery services and restaurant menus

Marginal increase of sunitinib exposure by grapefruit juice

Clinical Oncolog

Toward a Detailed Description of the Thermally Induced Dynamics of the Core Promoter

Establishing the general and promoter-specific mechanistic features of gene transcription initiation requires improved understanding of the sequence-dependent structural/dynamic features of promoter DNA. Experimental data suggest that a spontaneous dsDNA strand separation at the transcriptional start site is likely to be a requirement for transcription initiation in several promoters. Here, we use Langevin molecular dynamic simulations based on the Peyrard-Bishop-Dauxois nonlinear model of DNA (PBD LMD) to analyze the strand separation (bubble) dynamics of 80-bp-long promoter DNA sequences. We derive three dynamic criteria, bubble probability, bubble lifetime, and average strand separation, to characterize bubble formation at the transcriptional start sites of eight mammalian gene promoters. We observe that the most stable dsDNA openings do not necessarily coincide with the most probable openings and the highest average strand displacement, underscoring the advantages of proper molecular dynamic simulations. The dynamic profiles of the tested mammalian promoters differ significantly in overall profile and bubble probability, but the transcriptional start site is often distinguished by large (longer than 10 bp) and long-lived transient openings in the double helix. In support of these results are our experimental transcription data demonstrating that an artificial bubble-containing DNA template is transcribed bidirectionally by human RNA polymerase alone in the absence of any other transcription factors

Low pre-transplant levels of mannosebinding lectin are associated with viral infections and mortality after haematopoietic allogeneic stem cell transplantation

Background: Mannose-binding lectin (MBL) is a key component of innate immunity. Low serum MBL levels, related to promoter polymorphism and structural variants, have been associated with an increased risk of infection. The aim of this work was to analyse the incidence and severity of infections and mortality in relation to the MBL2 genotype and MBL levels in patients underwent allogeneic haematopoietic stem cell transplantation (Allo-HSCT). Results: This was a prospective cohort study of 72 consecutive patients underwent Allo-HSCT between January 2007 and June 2009 in a tertiary referral centre. Three periods were considered in the patients? follow-up: the early period (0?30 days after Allo-HSCT), the intermediate period (30?100 days after Allo-HSCT) and the late period (> 100 days after Allo-HSCT). A commercial line probe assay for MBL2 genotyping and an ELISA Kit were used to measure MBL levels. A total of 220 episodes of infection were collected in the 72 patients. No association between donor or recipient MBL2 genotype and infection was found. The first episode of infection presented earlier in patients with pre-transplant MBL levels of < 1000 ng/ml (median 6d vs 8d, p = 0.036). MBL levels < 1000 ng/ml in the pre-transplant period (risk ratio (RR) 2.48, 95% CI 1.00?6.13), neutropenic period (0?30 days, RR 3.28, 95% CI 1.53?7.06) and intermediate period (30?100 days, RR 2.37, 95% CI 1.15?4.90) were associated with increased risk of virus infection. No association with bacterial or fungal disease was found. Mortality was associated with pre-transplant MBL levels < 1000 ng/ml (hazard ratio 5.55, 95% CI 1.17?26.30, p = 0.03) but not with MBL2 genotype. Conclusions: Patients who underwent Allo-HSCT with low pre-transplant MBL levels presented the first episode of infection earlier and had an increased risk of viral infections and mortality in the first 6 months post-transplant. Thus, pre-transplant MBL levels would be important in predicting susceptibility to viral infections and mortality and might be considered a biomarker to be included in the pre-transplantation risk assessment.This work was supported by grants from the Fondo de Investigaciones Sanitarias (Ministry of Health of Spain) PI04/0492 to MC Fariñas and Instituto de Investigación Sanitaria Valdecilla (IDIVAL) API 06/01. The content of the paper is solely the responsibility of the authors and does not necessarily represent the official views. The funding body was not involved in the design of the study, collection or analysis of the data, interpretation of the data, or in the writing of the manuscript