Aim Method Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear... Show moreAim Method Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI. Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087). Results Conclusion We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol-related side effects. In a case-control study, the DDI was not significantly associated with bradycardia. Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta-blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol-related side effects is necessary. Show less
Niemeyer-van der Kolk, T.; Wall, H.E.C. van der; Balmforth, C.; Doorn, M.B.A. van; Rissmann, R. 2018
AimsTo explore the potential of the skin microbiome as biomarker in six dermatological conditions: atopic dermatitis (AD), acne vulgaris (AV), psoriasis vulgaris (PV), hidradenitis suppurativa (HS)... Show moreAimsTo explore the potential of the skin microbiome as biomarker in six dermatological conditions: atopic dermatitis (AD), acne vulgaris (AV), psoriasis vulgaris (PV), hidradenitis suppurativa (HS), seborrhoeic dermatitis/pityriasis capitis (SD/PC) and ulcus cruris (UC).MethodsA systematic literature review was conducted according to the PRISMA guidelines. Two investigators independently reviewed the included studies and ranked the suitability microbiome implementation for early phase clinical studies in an adapted GRADE method.ResultsIn total, 841 papers were identified and after screening of titles and abstracts for eligibility we identified 42 manuscripts that could be included in the review. Eleven studies were included for AD, five for AV, 10 for PV, two for HS, four for SD and 10 for UC. For AD and AV, multiple studies report the relationship between the skin microbiome, disease severity and clinical response to treatment. This is currently lacking for the remaining conditions.ConclusionFor two indications - AD and AV - there is preliminary evidence to support implementation of the skin microbiome as biomarkers in early phase clinical trials. For PV, UC, SD and HS there is insufficient evidence from the literature. More microbiome-directed prospective studies studying the effect of current treatments on the microbiome with special attention for patient meta-data, sampling methods and analysis methods are needed to draw more substantial conclusions. Show less
AimsSeveral studies have reported the under-representation of women in clinical trials, thereby challenging the external validity of the benefit/risk assessments of launched drugs. Our aim was to... Show moreAimsSeveral studies have reported the under-representation of women in clinical trials, thereby challenging the external validity of the benefit/risk assessments of launched drugs. Our aim was to determine the extent to which women have been included in clinical trials used for drug registration and to analyse the fraction of women participating in phases I, II and III.MethodsWe conducted cross-sectional, structured research into publicly available registration dossiers of Food and Drug Administration (FDA)-approved drugs that are prescribed frequently. Furthermore, we analysed compounds with high hepatic clearance and a known gender-related difference in drug response. In a sensitivity analysis, we compared figures with US disease prevalence data.ResultsFor 38 of the initial 137 drugs (28%), sufficient data were reported and publicly available. For these drugs, 185479 trial participants were included, of whom 47% were female and 44% were male; gender was not reported for 9% of participants. However, the number of female participants varied with the phase of the trial, with 22% females in phase I trials vs. 48% and 49%, respectively, in phase II and III trials. When compared with US disease prevalence data, 10 drugs (26%) had a greater than 20% difference between the proportion of females affected with the disease compared with representation in clinical trials.ConclusionsFrom these publicly available data, there was no evidence of any systematic under-representation of women in clinical trials. Show less
Figueroa, C.A.; Mocking, R.J.T.; Mahmoud, G.A.; Koeter, M.W.; Bockting, C.L.; Does, W. van der; ... ; Schene, A.H. 2018
Aims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed... Show moreAims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model in both critically ill children and other populations in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was externally evaluated in 136 individuals, including (pre)term neonates, infants, children, and adults (body weight 0.77-90 kg, CRP 0.1-341 mg/L and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in post-operative or critically ill paediatric patients and term neonates (median prediction error (MPE) <30%). Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation, and organ failure in children yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children, and adults with varying levels of critical illness including healthy adults, but not for extrapolation to preterm neonates. Show less
Jong, C. de; Sanders, S.; Creemers, G.J.; Burylo, A.M.; Taks, M.; Schellens, J.H.M.; Deenen, M.J. 2017
Aims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed... Show moreAims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model in both critically ill children and other populations in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was externally evaluated in 136 individuals, including (pre)term neonates, infants, children, and adults (body weight 0.77-90 kg, CRP 0.1-341 mg/L and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in post-operative or critically ill paediatric patients and term neonates (median prediction error (MPE) 180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation, and organ failure in children yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children, and adults with varying levels of critical illness including healthy adults, but not for extrapolation to preterm neonates. Show less
