Human hepatocyte assessment of imatinib drug–drug interactions – complexities in clinical translation

Aim

Inducers and inhibitors of CYP3A, such as ritonavir and efavirenz, may be used as part of the highly active antiretroviral therapy (HAART) to treat HIV patients. HIV patients with chronic myeloid leukemia or gastrointestinal stromal tumour may need imatinib, a CYP3A4 substrate with known exposure response–relationships. Administration of imatinib to patients on ritonavir or efavirenz may result in altered imatinib exposure leading to increased toxicity or failure of therapy, respectively. We used primary human hepatocyte cultures to evaluate the magnitude of interaction between imatinib and ritonavir/efavirenz.

Methods

Hepatocytes were pre-treated with vehicle, ritonavir, ketoconazole, efavirenz or rifampicin, and the metabolism of imatinib was characterized over time. Concentrations of imatinib and metabolite were quantitated in combined lysate and medium, using LC-MS.

Results

The predicted changes in imatinib CL_oral (95% CI) with ketoconazole, ritonavir, rifampicin and efavirenz were 4.0-fold (0, 9.2) lower, 2.8-fold (0.04, 5.5) lower, 2.9-fold (2.2, 3.5) higher and 2.0-fold (0.42, 3.5) higher, respectively. These predictions were in good agreement with clinical single dose drug–drug interaction studies, but not with reports of imatinib interactions at steady-state. Alterations in metabolism were similar after acute or chronic imatinib exposure.

Conclusions

In vitro human hepatocytes predicted increased clearance of imatinib with inducers and decreased clearance with inhibitors of CYP enzymes. The impact of HAART on imatinib may depend on whether it is being initiated or has already been dosed chronically in patients. Therapeutic drug monitoring may have a role in optimizing imatinib therapy in this patient population.     

Evaluation of Patients under Investigation for MERS-CoV Infection,United States,January 2013–October 2014

Middle East respiratory syndrome (MERS) cases continue to be reported from the Middle East. Evaluation and testing of patients under investigation (PUIs) for MERS are recommended. In 2013–2014, two imported cases were detected among 490 US PUIs. Continued awareness is needed for early case detection and implementation of infection control measures.     

Evaluating Epidemiology and Improving Surveillance of Infections Associated with Health Care,United States

The Healthcare-Associated Infections Community Interface (HAIC), launched in 2009, is the newest major activity of the Emerging Infections Program. The HAIC activity addresses population- and laboratory-based surveillance for Clostridium difficile infections, candidemia, and multidrug-resistant gram-negative bacilli. Other activities include special projects: the multistate Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey and projects that evaluate new approaches for improving surveillance. The HAIC activity has provided information about the epidemiology and adverse health outcomes of health care–associated infections and antimicrobial drug use in the United States and informs efforts to improve patient safety through prevention of these infections.     

Twenty Years of Active Bacterial Core Surveillance

Active Bacterial Core surveillance (ABCs) was established in 1995 as part of the Centers for Disease Control and Prevention Emerging Infections Program (EIP) network to assess the extent of invasive bacterial infections of public health importance. ABCs is distinctive among surveillance systems because of its large, population-based, geographically diverse catchment area; active laboratory-based identification of cases to ensure complete case capture; detailed collection of epidemiologic information paired with laboratory isolates; infrastructure that allows for more in-depth investigations; and sustained commitment of public health, academic, and clinical partners to maintain the system. ABCs has directly affected public health policies and practices through the development and evaluation of vaccines and other prevention strategies, the monitoring of antimicrobial drug resistance, and the response to public health emergencies and other emerging infections.     

Cancers in Australia in 2010 attributable to total breastfeeding durations of 12 months or less by parous women

Objectives: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to parous women having breastfed for total durations of ≤12 months. Methods: We estimated the population attributable fraction (PAF) of breast cancers (the only cancer site with convincing evidence of causal association) associated with women breastfeeding for ≤12 months in total, using standard formulae incorporating breastfeeding prevalence data, relative risks associated with breastfeeding and cancer incidence. We also estimated the proportion change in disease incidence (potential impact fraction [PIF]) that might have occurred under two hypothetical scenarios of women breastfeeding for longer durations. Results: An estimated 235 (1.7%) breast cancer cases that occurred in Australian in 2010 could be attributed to women breastfeeding for total durations of ≤12 months. Assuming a hypothetical increase in breastfeeding, we estimated that the number of breast cancers prevented would range from 36 to 51 (prevented fraction = 0.3% to 0.4%). Conclusions: More than 200 breast cancers were attributable to women breastfeeding for total durations of ≤12 months. Implications: Policies to increase breastfeeding duration may help prevent breast cancers in the future.     

Care planning for long‐term conditions – a concept mapping

Objective

This article focuses on approaches within clinical practice that seek to actively involve patients with long‐term conditions (LTCs) and how professionals may understand and implement them. Personalized care planning is one such approach, but its current lack of conceptual clarity might have impeded its widespread implementation to date. A variety of overlapping concepts coexist in the literature, which have the potential to impair both clinical and research agendas. The aim of this article is therefore to explore the meaning of the concept of care planning in relation to other overlapping concepts and how this translates into clinical practice implementation.

Methods

Searches were conducted in the Cochrane database for systematic reviews, CINHAL and MEDLINE. A staged approach to conducting the concept mapping was undertaken, by (i) an examination of the literature on care planning in LTCs; (ii) identification of related terms; (iii) locating reviews of those terms. Retrieved articles were subjected to a content analysis, which formed the basis of our concept maps. (iv) We then appraised these against knowledge and experience of the implementation of care planning in clinical practice.

Results and Conclusions

Thirteen articles were retrieved, in which the core importance of patient‐centredness, shared decision making and self‐management was highlighted. Literature searches on these terms retrieved a further 24 articles. Our concept mapping exercise shows that whilst there are common themes across the concepts, the differences between them reflect the context and intended outcomes within clinical practice. We argue that this clarification exercise will allow for further development of both research and clinical implementation agendas.