Pharmacogenetic Analysis of Voriconazole Treatment in Children

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections. Keywords: ABCC2; ABCG2; CYP2C19; CYP3A4; children; non-linear mixed effects modelling; pediatric pharmacology; pharmacogenetics; therapeutic drug monitoring; voriconazol

Physical activity through sustainable transport approaches (PASTA): protocol for a multi-centre, longitudinal study

BACKGROUND: Physical inactivity is one of the leading risk factors for non-communicable diseases, yet many are not sufficiently active. The Physical Activity through Sustainable Transport Approaches (PASTA) study aims to better understand active mobility (walking and cycling for transport solely or in combination with public transport) as an innovative approach to integrate physical activity into individuals' everyday lives. The PASTA study will collect data of multiple cities in a longitudinal cohort design to study correlates of active mobility, its effect on overall physical activity, crash risk and exposure to traffic-related air pollution. METHODS/DESIGN: A set of online questionnaires incorporating gold standard approaches from the physical activity and transport fields have been developed, piloted and are now being deployed in a longitudinal study in seven European cities (Antwerp, Barcelona, London, Oerebro, Rome, Vienna, Zurich). In total, 14000 adults are being recruited (2000 in each city). A first questionnaire collects baseline information; follow-up questionnaires sent every 13 days collect prospective data on travel behaviour, levels of physical activity and traffic safety incidents. Self-reported data will be validated with objective data in subsamples using conventional and novel methods. Accelerometers, GPS and tracking apps record routes and activity. Air pollution and physical activity are measured to study their combined effects on health biomarkers. Exposure-adjusted crash risks will be calculated for active modes, and crash location audits are performed to study the role of the built environment. Ethics committees in all seven cities have given independent approval for the study. DISCUSSION: The PASTA study collects a wealth of subjective and objective data on active mobility and physical activity. This will allow the investigation of numerous correlates of active mobility and physical activity using a data set that advances previous efforts in its richness, geographical coverage and comprehensiveness. Results will inform new health impact assessment models and support efforts to promote and facilitate active mobility in cities

Health impact assessment of active transportation: A systematic review

Objective Walking and cycling for transportation (i.e. active transportation, AT), provide substantial health benefits from increased physical activity (PA). However, risks of injury from exposure to motorized traffic and their emissions (i.e. air pollution) exist. The objective was to systematically review studies conducting health impact assessment (HIA) of a mode shift to AT on grounds of associated health benefits and risks. Methods Systematic database searches of MEDLINE, Web of Science and Transportation Research International Documentation were performed by two independent researchers, augmented by bibliographic review, internet searches and expert consultation to identify peer-reviewed studies from inception to December 2014. Results Thirty studies were included, originating predominantly from Europe, but also the United States, Australia and New Zealand. They compromised of mostly HIA approaches of comparative risk assessment and cost–benefit analysis. Estimated health benefit–risk or benefit–cost ratios of a mode shift to AT ranged between − 2 and 360 (median = 9). Effects of increased PA contributed the most to estimated health benefits, which strongly outweighed detrimental effects of traffic incidents and air pollution exposure on health. Conclusion Despite different HIA methodologies being applied with distinctive assumptions on key parameters, AT can provide substantial net health benefits, irrespective of geographical context

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme

Gentamicin Population Pharmacokinetics in Pediatric Patients-A Prospective Study with Data Analysis Using the saemix Package in R

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children's Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPK$^{cdw}$ platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0-21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment

Gentamicin Population Pharmacokinetics in Pediatric Patients—A Prospective Study with Data Analysis Using the saemix Package in R

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children’s Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0–21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment