Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS • A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h−1) = 11.4 × (WT/70.0)0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h−1 and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS The range of estimated CL/F in the study population was 0.67–7.38 l h−1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Development of a physiologically-based pharmacokinetic model of the rat central nervous system

Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.

Sales manager and sales team determinants of salesperson ethical behaviour

Purpose – The purpose of this paper is to develop and test a model of the role managers and peers play in shaping salespeople's ethical behaviour. The model specifies that sales manager personal moral philosophies, whether sales managers themselves are rewarded according to the outcomes or behaviours of their salespeople, sales team job security, intra-team cooperation, and sales team tactical performance all influence sales team ethical standards. In turn, ethical standards influence the probability that sales team members will behave (un)ethically when faced with ethical dilemmas. Design/methodology/approach – The model is tested on a sample of 154 Finnish sales managers. Data were collected via mail survey. Analysis was undertaken using structural equation modelling. Findings – Ethical standards appear to be shaped by several factors; behaviour-based management controls increase ethical standards, relativist managers tend to manage less ethically-minded sales teams, job insecurity impedes the development of ethical standards, and sales teams' cooperation activity increases ethical standards. Sales teams are less likely to engage in unethical behaviour when the teams have strong ethical standards. Research limitations/implications – Cross-sectional data limits generalisability; single country data may limit the ability to generalise to different sales environments; additional measure development is needed; identification of additional antecedent factors would be beneficial. Practical implications – Sales managers should consciously develop high ethical standards in sales teams if they wish to reduce unethical behaviour. Ethical standards can be improved if sales managers change their own outward behaviour (exhibit a less relativistic ethical philosophy), foster cooperation amongst salespeople, and develop perceptions of job security. How sales managers are rewarded may shape how they approach the management of ethical behaviour in their sales teams. Originality/value – This paper appears to be the first to simultaneously examine both sales manager-specific and sales team-specific antecedents to sales team ethical standards and behaviours. As such, it provides an important base for research in this critical area.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims - To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods - The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results - The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)0.35 x EXP (-0.0058 x TPT) x EXP (0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself. • Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDS • The first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed. • The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates. • The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS - To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS - Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS - The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS - The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

An operational research-based integrated approach for mass evacuation planning of a city

Large-scale disasters are constantly occurring around the world, and in many cases evacuation of regions of city is needed. ‘Operational Research/Management Science’ (OR/MS) has been widely used in emergency planning for over five decades. Warning dissemination, evacuee transportation and shelter management are three ‘Evacuation Support Functions’ (ESF) generic to many hazards. This thesis has adopted a case study approach to illustrate the importance of integrated approach of evacuation planning and particularly the role of OR/MS models. In the warning dissemination phase, uncertainty in the household’s behaviour as ‘warning informants’ has been investigated along with uncertainties in the warning system. An agentbased model (ABM) was developed for ESF-1 with households as agents and ‘warning informants’ behaviour as the agent behaviour. The model was used to study warning dissemination effectiveness under various conditions of the official channel. In the transportation phase, uncertainties in the household’s behaviour such as departure time (a function of ESF-1), means of transport and destination have been. Households could evacuate as pedestrians, using car or evacuation buses. An ABM was developed to study the evacuation performance (measured in evacuation travel time). In this thesis, a holistic approach for planning the public evacuation shelters called ‘Shelter Information Management System’ (SIMS) has been developed. A generic allocation framework of was developed to available shelter capacity to the shelter demand by considering the evacuation travel time. This was formulated using integer programming. In the sheltering phase, the uncertainty in household shelter choices (either nearest/allocated/convenient) has been studied for its impact on allocation policies using sensitivity analyses. Using analyses from the models and detailed examination of household states from ‘warning to safety’, it was found that the three ESFs though sequential in time, however have lot of interdependencies from the perspective of evacuation planning. This thesis has illustrated an OR/MS based integrated approach including and beyond single ESF preparedness. The developed approach will help in understanding the inter-linkages of the three evacuation phases and preparing a multi-agency-based evacuation planning evacuation

Generic experiments at the sump model "Zittauer Strömungswanne" (ZSW) for the behaviour of mineral wool in the sump and the reactor core

The investigation of insulation debris transport, sedimentation, penetration into the reactor core and head loss build up becomes important to reactor safety research for PWR and BWR, when considering the long-term behaviour of emergency core cooling systems during loss of coolant accidents. Research projects are being performed in cooperation between the University of Applied Sciences Zittau/Görlitz and the Helmholtz-Zentrum Dresden-Rossendorf. The projects include experimental investigations of different processes and phenomena of insulation debris in coolant flow and the development of CFD models. Generic complex experiments serve for building up a data base for the validation of models for single effects and their coupling in CFD codes. This paper includes the description of the experimental facility for complex generic experiments (ZSW), an overview about experimental boundary conditions and results for upstream and down-stream phenomena as well as for the long-time behaviour due to corrosive processes. © Carl Hanser Verlag, München.

Collective behaviour in a square lattice of driven Duffing resonators coupled to van der Pol oscillators

The global and local synchronisation of a square lattice composed of alternating Duffing resonators and van der Pol oscillators coupled through displacement is studied. The lattice acts as a sensing device in which the input signal is characterised by an external driving force that is injected into the system through a subset of the Duffing resonators. The parameters of the system are taken from MEMS devices. The effects of the system parameters, the lattice architecture and size are discussed.

Health beliefs affect the correct replacement of daily disposable contact lenses:predicting compliance with the Health Belief Model and the Theory of Planned Behaviour

Purpose: To assess the compliance of Daily Disposable Contact Lenses (DDCLs) wearers with replacing lenses at a manufacturer-recommended replacement frequency. To evaluate the ability of two different Health Behavioural Theories (HBT), The Health Belief Model (HBM) and The Theory of Planned Behaviour (TPB), in predicting compliance. Method: A multi-centre survey was conducted using a questionnaire completed anonymously by contact lens wearers during the purchase of DDCLs. Results: Three hundred and fifty-four questionnaires were returned. The survey comprised 58.5% females and 41.5% males (mean age 34. ±. 12. years). Twenty-three percent of respondents were non-compliant with manufacturer-recommended replacement frequency (re-using DDCLs at least once). The main reason for re-using DDCLs was "to save money" (35%). Predictions of compliance behaviour (past behaviour or future intentions) on the basis of the two HBT was investigated through logistic regression analysis: both TPB factors (subjective norms and perceived behavioural control) were significant (p. <. 0.01); HBM was less predictive with only the severity (past behaviour and future intentions) and perceived benefit (only for past behaviour) as significant factors (p. <. 0.05). Conclusions: Non-compliance with DDCLs replacement is widespread, affecting 1 out of 4 Italian wearers. Results from the TPB model show that the involvement of persons socially close to the wearers (subjective norms) and the improvement of the procedure of behavioural control of daily replacement (behavioural control) are of paramount importance in improving compliance. With reference to the HBM, it is important to warn DDCLs wearers of the severity of a contact-lens-related eye infection, and to underline the possibility of its prevention.