In the majority of cases, there is no difficulty in diagnosing Cystic Fibrosis (CF). However, there may be wide variation in signs and symptoms between individuals which encourage the scientific community to constantly improve the diagnostic tests available and develop better methods to come to a final diagnosis in patients with milder phenotypes. This paper is the result of discussions held at meetings of the European Cystic Fibrosis Society Diagnostic Network supported by EuroCareCF. CFTR bioassays in the nasal epithelium (nasal potential difference measurements) and the rectal mucosa (intestinal current measurements) are discussed in detail including efforts to standardize the techniques across Europe. New approaches to evaluate the sweat gland, future of genetic testing and methods on the horizon like CFTR expression in human leucocytes and erythrocytes are discussed briefly.

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis.Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts.The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed.This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

Background Ivacaftor (Kalydeco) is the first drug to treat the molecular defect underlying cystic fibrosis (CF). To this end the substance appears to be effective only in patients with the G551D mutation in the CFTR gene. Due to the low number of patients currently treated, very little is known about the PK/PD relationship of ivacaftor. Purpose Serum concentration measurements were used in order to control for adherence, to rule out dose-dependent side effects and to better understand the pharmacokinetics of ivacaftor. Materials and methods Serum samples were obtained 3–4 h after intake of 150 mg ivacaftor by patients who had been treated with Kalydeco for at least 3 months. After deproteinisation, ivacaftor serum concentrations were determined using validated liquid chromatography with mass spectroscopic detection (LC-MS Q-TOF). Results We were able to observe blood samples from 6 patients without impaired hepatic function and without co-administration of other CYP3 inhibitors. All were taking the standard dose of 2 × 150 mg/d. The ivacaftor levels appeared to vary from 400 to 3000 ng/ml. 5 of the 6 patients had significantly higher levels than those reported from the pivotal trials for ivacaftor. Conclusions Our initial results demonstrated that ivacaftor serum levels in patients treated with the standard dosing scheme for ivacaftor (150 mg bid) were much higher than reported in the literature. Given the background information reported by the manufacturers in the SPC that an effective concentration 90% (EC90) is 405 ng/mL a dose reduction could be considered. No conflict of interest.

BackgroundThe Directive 2011/62/EU (Falsified medicines directive, FMD) provides for measures to prevent the entry into the legal supply chain of falsified medicinal products and has been supplemented by the commission delegated regulation (EU) 2016/161. From February 2019 onwards prescription medicines are required to bear individual safety features that need to be verified and decommissioned by pharmacies before being supplied to the public. While this process has already been tested in some community pharmacies, little is known on the implications the FMD has on healthcare institutions.PurposeAim of the present study was to assess the impact of the implementation of the FMD in a university-based hospital pharmacy that currently provides medicines for approximately 2000 beds and prepares more than 55 000 chemotherapies per year.Material and methodsIn order to simulate the ‘end-to-end’ verification as outlined by the directive, packs of prescription medicines were scanned at goods in and at several points of dispense within the pharmacy. The time required to process the respective number of drugs was measured and clustered for the individual product type.ResultsA total of 1546 packs of 59 different medicinal products were assessed at goods in, which took a median of 2.1 s (0.6–6. 5 s) to process each single pack. However, some drugs such as iv-anaesthetics, iv-antibiotics and iv-painkillers, all of which were stored on pallets, required a significantly higher amount of time to verify. The simulation was repeated at four different points of dispense where 2056 packs of 811 different drugs were scanned. Here the amount of time required was not significantly different (median 2 s) from goods in but with a higher variation between the different products. Based on these data we extrapolated that the amount of time needed to process the 2.8 million packs of prescription drugs supplied by our pharmacy is more than 1,500 hours per year.ConclusionOur study demonstrates that the implementation of the FMD in the hospital pharmacy is a major challenge. Compared with the community pharmacy, a much greater degree of planning, organisation and technical support is needed to cope with the decommissioning of large numbers of drugs.References and/or Acknowledgements1. FMD:https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2011_62/dir_2011_62_en.pdf2. Commission Delegated Regulation (EU) 2016/161: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2016_161/reg_2016_161_en.pdfNo conflict of interest

No abstract