Bayesian population pharmacokinetic analysis of sirolimus

Objective: It is usual that data collected from routine clinical care is sparse and unable to support the more complex pharmacokinetic (PK) models that may have been reported in previous rich data studies. Informative priors may be a pre-requisite for model development. The aim of this study was to estimate the population PK parameters of sirolimus using a fully Bayesian approach with informative priors. Methods: Informative priors including prior mean and precision of the prior mean were elicited from previous published studies using a meta-analytic technique. Precision of between-subject variability was determined by simulations from a Wishart distribution using MATLAB (version 6.5). Concentration-time data of sirolimus retrospectively collected from kidney transplant patients were analysed using WinBUGS (version 1.3). The candidate models were either one- or two-compartment with first order absorption and first order elimination. Model discrimination was based on computation of the posterior odds supporting the model. Results: A total of 315 concentration-time points were obtained from 25 patients. Most data were clustered at trough concentrations with range of 1.6 to 77 hours post-dose. Using informative priors, either a one- or two-compartment model could be used to describe the data. When a one-compartment model was applied, information was gained from the data for the value of apparent clearance (CL/F = 18.5 L/h), and apparent volume of distribution (V/F = 1406 L) but no information was gained about the absorption rate constant (ka). When a two-compartment model was fitted to the data, the data were informative about CL/F, apparent inter-compartmental clearance, and apparent volume of distribution of the peripheral compartment (13.2 L/h, 20.8 L/h, and 579 L, respectively). The posterior distribution of the volume distribution of central compartment and ka were the same as priors. The posterior odds for the two-compartment model was 8.1, indicating the data supported the two-compartment model. Conclusion: The use of informative priors supported the choice of a more complex and informative model that would otherwise have not been supported by the sparse data.

Paediatric population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in cystic fibrosis and bone marrow transplant patients

Objectives: The aim of the study was to characterise the population pharmacokinetics (popPK) properties of itraconazole (ITRA) and its active metabolite hydroxy-ITRA in a representative paediatric population of cystic fibrosis (CF) and bone marrow transplant (BMT) patients. The goals were to determine the relative bioavailability between the two oral formulations, and to explore improved dosage regimens in these patients. Methods: All paediatric patients with CF taking oral ITRA for the treatment of allergic bronchopulmonary aspergillosis and patients undergoing BMT who were taking ITRA for prophylaxis of any fungal infection were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. ITRA and hydroxy-ITRA plasma concentrations were measured by HPLC[1]. A nonlinear mixed-effect modelling approach (NONMEM 5.1.1) was used to describe the PK of ITRA and hydroxy-ITRA simultaneously. Simulations were used to assess dosing strategies in these patients. Results: Forty-nine patients (29CF, 20 BMT) were recruited to the study who provided 227 blood samples for the population analysis. A 1-compartment model with 1st order absorption and elimination best described ITRA kinetics, with 1st order conversion to hydroxy-ITRA. For ITRA, the apparent clearance (ClItra/F) and volume of distribution (Vitra/F) was 35.5L/h and 672L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h-1 and for the oral solution formulation it was 0.959 h-1. The capsule comparative bioavailability (vs. solution) was 0.55. For hydroxy-ITRA, the apparent volume of distribution and clearance were 10.6 L and 5.28 L/h, respectively. Of several screened covariates only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. Conclusion: The developed popPK model adequately described the pharmacokinetics of ITRA and hydroxy-ITRA in paediatric patients with CF and patients undergoing BMT. High inter-patient variability confirmed previous data in CF[2], leukaemia and BMT[3] patients. From the population model, simulations showed the standard dose (5 mg/kg/day) needs to be doubled for the solution formulation and even 4 times more given of the capsules to achieve an adequate target therapeutic trough plasma concentration of 0.5 mg/L[4] in these patients.

Learning to play Pac-Man: An evolutionary, rule-based approach

Pac-Man is a well-known, real-time computer game that provides an interesting platform for research. We describe an initial approach to developing an artificial agent that replaces the human to play a simplified version of Pac-Man. The agent is specified as a simple finite state machine and ruleset. with parameters that control the probability of movement by the agent given the constraints of the maze at some instant of time. In contrast to previous approaches, the agent represents a dynamic strategy for playing Pac-Man, rather than a pre-programmed maze-solving method. The agent adaptively "learns" through the application of population-based incremental learning (PBIL) to adjust the agents' parameters. Experimental results are presented that give insight into some of the complexities of the game, as well as highlighting the limitations and difficulties of the representation of the agent.

A heuristic approach for component scheduling on a high-speed PCB assembly machine

The collect-and-place machine is one of the most widely used placement machines for assembling electronic components on the printed circuit boards (PCBs). Nevertheless, the number of researches concerning the optimisation of the machine performance is very few. This motivates us to study the component scheduling problem for this type of machine with the objective of minimising the total assembly time. The component scheduling problem is an integration of the component sequencing problem, that is, the sequencing of component placements; and the feeder arrangement problem, that is, the assignment of component types to feeders. To solve the component scheduling problem efficiently, a hybrid genetic algorithm is developed in this paper. A numerical example is used to compare the performance of the algorithm with different component grouping approaches and different population sizes.

Typical kernel size and number of sparse random matrices over Galois fields: a statistical physics approach

Using methods of statistical physics, we study the average number and kernel size of general sparse random matrices over GF(q), with a given connectivity profile, in the thermodynamical limit of large matrices. We introduce a mapping of GF(q) matrices onto spin systems using the representation of the cyclic group of order q as the q-th complex roots of unity. This representation facilitates the derivation of the average kernel size of random matrices using the replica approach, under the replica symmetric ansatz, resulting in saddle point equations for general connectivity distributions. Numerical solutions are then obtained for particular cases by population dynamics. Similar techniques also allow us to obtain an expression for the exact and average number of random matrices for any general connectivity profile. We present numerical results for particular distributions.

Meta-analysis of the population and phenotypic expression of CYP2C9/2C19 polymorphism on drug metabolism in different ethnicities

The term "pharmacogenetics" has been defined as the scientific study of inherited factors that affect the human drug response. Many pharmacogenetie studies have been published since 1995 and have focussed on the principal enzyme family involved in drug metabolism, the cytochrome P450 family, particularly cytochrome P4502C9 and 2C19. In order to investigate the pharmacogenetic aspect of pharmacotherapy, the relevant studies describing the association of pharmacogenetic factor(s) in drug responses must be retrieved from existing literature using a systematic review approach. In addition, the estimation of variant allele prevalence for the gene under study between different ethnic populations is important for pharmacogenetic studies. In this thesis, the prevalence of CYP2C9/2C19 alleles between different ethnicities has been estimated through meta-analysis and the population genetic principle. The clinical outcome of CYP2C9/2C19 allelic variation on the pharmacotherapy of epilepsy has been investigated; although many new antiepileptic drugs have been launched into the market, carbamazepine, phenobarbital and phenytoin are still the major agents in the pharmacotherapy of epilepsy. Therefore, phenytoin was chosen as a model AED and the effect of CYP2C9/2C19 genetic polymorphism on phenytoin metabolism was further examined.An estimation of the allele prevalence was undertaken for three CYP2C9/2C19 alleles respectively using a meta-analysis of studies that fit the Hardy-Weinberg equilibrium. The prevalence of CYP2C9*1 is approximately 81%, 96%, 97% and 94% in Caucasian, Chinese, Japanese, African populations respectively; the pooled prevalence of CYP2C19*1 is about 86%, 57%, 58% and 85% in these ethnic populations respectively. However, the studies of association between CYP2C9/2C19 polymorphism and phenytoin metabolism failed to achieve any qualitative or quantitative conclusion. Therefore, mephenytoin metabolism was examined as a probe drug for association between CYP2C19 polymorphism and mephenytoin metabolic ratio. Similarly, analysis of association between CYP2C9 polymorphism and warfarin dose requirement was undertaken.It was confirmed that subjects carrying two mutated CYP2C19 alleles have higher S/R mephenytoin ratio due to deficient CYP2C19 enzyme activity. The studies of warfarin and CYP2C9 polymorphism did not provide a conclusive result due to poor comparability between studies.The genetic polymorphism of drug metabolism enzymes has been studied extensively, however other genetic factors, such as multiple drug resistance genes (MDR) and genes encoding ion channels, which may contribute to variability in function of drug transporters and targets, require more attention in future pharmacogenetic studies of antiepileptic drugs.

An integrative approach to developing an intercultural awareness strategy in a multicultural university

Universities are increasingly diverse places; in terms of staff and students, their nationality, ethnicity and religious backgrounds. HEIs need to find ways of ensuring that this diversity adds to the life of the institution and to the development of graduates as employees in a global workplace. The paper offers a case study of one way of developing an intercultural strategy at a UK university. The university concerned has a highly multicultural and multinational staff and student population. Over many years the university has worked to celebrate and embed this diversity into the culture and values of the institution; in its learning, teaching, business operations and relationships. The university wished to develop its intercultural awareness strategy in an inspirational and vibrant way, one which was informed by research and practice. The paper proposes a new integrative approach to developing an intercultural strategy, and summarises some reflections on the process of creating the intercultural awareness strategy which may be of use to other institutions. Analysis showed that in order to make the strategy effective there had to be commitment from senior management to match innovative practices at an individual level. It is also clear that such a strategy must include formal policies and procedures, as well as more informal channels to allow people to express intercultural differences and shared values. The critical role of middle management in strategy implementation is also discussed.

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.

Improving T cell-induced response to subunit vaccines:opportunities for a proteomic systems approach

Prophylactic vaccines are an effective strategy to prevent development of many infectious diseases. With new and re-emerging infections posing increasing risks to food stocks and the health of the population in general, there is a need to improve the rationale of vaccine development. One key challenge lies in development of an effective T cell-induced response to subunit vaccines at specific sites and in different populations. Objectives: In this review, we consider how a proteomic systems-based approach can be used to identify putative novel vaccine targets, may be adopted to characterise subunit vaccines and adjuvants fully. Key findings: Despite the extensive potential for proteomics to aid our understanding of subunit vaccine nature, little work has been reported on identifying MHC 1-binding peptides for subunit vaccines generating T cell responses in the literature to date. Summary: In combination with predictive and structural biology approaches to mapping antigen presentation, proteomics offers a powerful and as yet un-tapped addition to the armoury of vaccine discovery to predict T-cell subset responses and improve vaccine design strategies.

Regional growth and SMEs in Brazil:a spatial panel approach

Cravo T. A., Becker B. and Gourlay A. Regional growth and SMEs in Brazil: a spatial panel approach, Regional Studies. This paper examines economic growth for a panel of 508 Brazilian micro-regions for the period 1980-2004, using spatial econometrics and paying particular attention to the importance of small and medium-sized enterprises (SMEs). The findings indicate the presence of spatial dependence in the process of economic growth and the existence of two spatial regimes in Brazil. The human capital level of the whole population is an important growth determinant, but does not generate positive spillovers. Furthermore, human capital embodied in SMEs is more important than the size of this sector for regional growth and SME activity generates positive spatial spillovers. © 2014 © 2014 Regional Studies Association.

A new VRPPD model and a hybrid heuristic solution approach for e-tailing

We analyze a business model for e-supermarkets to enable multi-product sourcing capacity through co-opetition (collaborative competition). The logistics aspect of our approach is to design and execute a network system where “premium” goods are acquired from vendors at multiple locations in the supply network and delivered to customers. Our specific goals are to: (i) investigate the role of premium product offerings in creating critical mass and profit; (ii) develop a model for the multiple-pickup single-delivery vehicle routing problem in the presence of multiple vendors; and (iii) propose a hybrid solution approach. To solve the problem introduced in this paper, we develop a hybrid metaheuristic approach that uses a Genetic Algorithm for vendor selection and allocation, and a modified savings algorithm for the capacitated VRP with multiple pickup, single delivery and time windows (CVRPMPDTW). The proposed Genetic Algorithm guides the search for optimal vendor pickup location decisions, and for each generated solution in the genetic population, a corresponding CVRPMPDTW is solved using the savings algorithm. We validate our solution approach against published VRPTW solutions and also test our algorithm with Solomon instances modified for CVRPMPDTW.

A computational approach to unbiased districting

In the context of discrete districting problems with geographical constraints, we demonstrate that determining an (ex post) unbiased districting, which requires that the number of representatives of a party should be proportional to its share of votes, turns out to be a computationally intractable (NP-complete) problem. This raises doubts as to whether an independent jury will be able to come up with a “fair” redistricting plan in case of a large population, that is, there is no guarantee for finding an unbiased districting (even if such exists). We also show that, in the absence of geographical constraints, an unbiased districting can be implemented by a simple alternating-move game among the two parties.

The effect of climate change on the potential distribution of the European Phlebotomus species and the parasite Leishmania infantum in 2011-2070. A climate envelope modeling approach

Aims: In the Mediterranean areas of Europe, leishmanisasis is one of the most emerging vector-borne diseases. Members of genus Phlebotomus are the primary vectors of the genus Leishmania. To track the human health effect of climate change it is a very important interdisciplinary question to study whether the climatic requirements and geographical distribution of the vectors of human pathogen organisms correlate with each other. Our study intended to explore the potential effects of ongoing climate change, in particular through a potential upward altitudinal and latitudinal shift of the distribution of the parasite Leishmania infantum, its vectors Phlebotomus ariasi, P. neglectus, P. perfiliewi, P. perniciosus, and P. tobbi, and some other sandfly species: P. papatasi, P. sergenti, and P. similis. Methods: By using a climate envelope modelling (CEM) method we modelled the current and future (2011-2070) potential distribution of 8 European sandfly species and L. infantum based on the current distribution using the REMO regional climate model. Results: We found that by the end of the 2060’s most parts of Western Europe can be colonized by sandfly species, mostly by P. ariasi and P. pernicosus. P. ariasi showed the greatest potential northward expansion. For all the studied vectors of L. infantum the entire Mediterranean Basin and South-Eastern Europe seemed to be suitable. L. infantum can affect the Eastern Mediterranean, without notable northward expansion. Our model resulted 1 to 2 months prolongation of the potentially active period of P. neglectus P. papatasi and P. perniciosus for the 2060’s in Southern Hungary. Conclusion: Our findings confirm the concerns that leishmanisais can become a real hazard for the major part of the European population to the end of the 21th century and the Carpathian Basin is a particularly vulnerable area.