Background and objectivesFostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects.MethodsThe OC study was a crossover study over two 28-day treatment periods (Microgynon® 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8–20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout.ResultsFostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration–time curve at steady state (AUCss) 28 % [confidence interval (CI 90 %) 21–36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34 % (CI 26–43)], but not levonorgestrel (AUCss 5 %; Cmax,ss −3 %), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈20 %). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18 % (CI 13–23) and 13 % (CI 7–19)]. Fostamatinib increased rosuvastatin AUC by 96 % (CI 78–115) and Cmax by 88 % (CI 69–110), and increased simvastatin acid AUC by 74 % (CI 50–102) and Cmax by 83 % (CI 57–113).ConclusionFostamatinib exhibits drug–drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-015-0120-x) contains supplementary material, which is available to authorized users.

Transporters are carrier proteins that may influence pharmacokinetic, pharmacodynamic, and toxicological characteristics of drugs. The development of validated in vitro transporter models is imperative to support regulatory submissions of drug candidates. This study is focused on utilizing human embryonic kidney (HEK) 293 cell cultures genetically transfected with the human organic anion transporting polypeptides (OATP) 1B1 transporter to identify substrates and inhibitors in drug development. The kinetics of OATP1B1-mediated uptake of [(3)H]-oestradiol 17beta-glucuronide and inhibition of uptake by rifamycin SV were used to determine K(m), V(max), and IC(50) values over a range of passage numbers to investigate accuracy and precision. The mean K(m) and V(max) values were found to be 6.3 +/- 1.2 microM and 460 +/- 96 pmol min(-1) mg(-1), respectively. The mean IC(50) value for rifamycin SV was 0.23 +/- 0.07 microM on uptake of 1 microM [(3)H]-oestradiol 17beta-glucuronide. These data were similar to previously reported values (accuracy greater than 82%), reproducible (precision less than 29%) and exhibited low standard deviations (SDs) obviating the need to study test compounds on more than one occasion. [(3)H]-oestrone 3-sulfate and [(3)H]-pravastatin exhibited concentration-dependent OATP1B1 uptake, and statistically significant differences were observed at each concentration between uptake rates of HEK293-OATP1B1 and HEK293-MOCK cells (uptake ratios greater than or equal to 3). Propranolol showed no positive uptake ratio. Bezafibrate and gemfibrozil exhibited concentration-dependent inhibition of OATP1B1-mediated uptake of [(3)H]-oestradiol 17beta-glucuronide with mean IC(50) values of 16 and 27 microM, respectively. Based on the validation results, acceptance criteria to identify a test compound as a substrate and/or inhibitor using these specific cell lines were determined. These validated OATP1B1 assays were robust, reproducible, and suitable for routine in vitro evaluation of candidate drugs.

Understanding parents' experience of care is essential to develop high-quality perinatal bereavement services. This study aimed at developing a questionnaire to identify parents' needs and record their experience of care. The patient experience questionnaire was developed by professionals and parents, and piloted in a tertiary maternity unit. Responses were received from 58 parents. Sensitivity and kindness of staff and time spent with their baby were ranked as 'very important' by 95% of parents. Care in these areas largely met their needs (90%), although 5% of respondents stated that partners could have been more involved. Between 8% and 15% of respondents did not feel that language used at the diagnosis of fetal death was sensitive, clear and unambiguous. Parents did not always receive written information about their care (5%) or post-mortem (13%). Analysis of bereaved parents' responses identified areas for improvement including greater involvement of partners and a need for timely information. Impact statement What is already known on this subject?: Good quality bereavement care after perinatal death reduces the negative emotional, psychological and social effects for parents. Description of parents' experiences is a potential means to improve the quality of perinatal bereavement care. What do the results of this study add?: Parents' needs and experiences of care after perinatal death were recorded using a patient-experience questionnaire designed by a multi-professional team and parents. Staff behaviour, particularly sensitivity and kindness was highly valued by parents. Giving both verbal and written information could be improved. Training is needed for professionals, particularly those who come into contact with bereaved parents less frequently. What are the implications of these findings for clinical practice and/or further research?: Description of parents' priorities and views can be used to identify areas for improvement in perinatal bereavement care. Parents' views should be regularly sought and used to develop local services in an iterative process.

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Two phase I open‐label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end‐stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of selumetinib 50 mg; those with ESRD received selumetinib before and after dialysis (with a between‐treatment washout period of ≥7 days). In the hepatic impairment study, subjects received varying single doses of selumetinib (20‐50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child‐Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose‐normalized total selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child‐Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound selumetinib exposure. In both studies, selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients.

Robust and sensitive LC-MS/MS assays for the quantification of selumetinib and two of its metabolites were validated in human biological matrices and are being used to support the clinical development program.

Female genital mutilation (FGM) is illegal in the UK but nevertheless practised in some immigrant communities. Effective educational approaches are required to inform policy and to direct resources, often in the voluntary sector. The opinions in this article arise from discussions with professionals and members of FGM-practising communities. We highlight the importance of sharing experiences and expertise across health and social care professionals as well as working in partnership with culturally sensitive Non-Governmental Organisations. Enlisting the support of men and religious leaders is crucial to breaking down barriers in male-dominated communities and dispelling myths about FGM being a 'requirement' of faith.

Selumetinib 75 mg did not cause any QT/QTc interval prolongation in these healthy subjects, and selumetinib is not expected to have a clinically relevant effect on cardiac repolarization in patients at the anticipated therapeutic dose of 75 mg. The model also demonstrated the low potential for any QTc effects of selumetinib at doses higher than the standard therapeutic dose.