Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Modeling of formation of gold nanoparticles by citrate method

Properties of nanoparticles are size dependent, and a model to predict particle size is of importance. Gold nanoparticles are commonly synthesized by reducing tetrachloroauric acid with trisodium citrate, a method pioneered by Turkevich et al (Discuss. Faraday Soc. 1951, 11, 55). Data from several investigators that used this method show that when the ratio of initial concentrations of citrate to gold is varied from 0.4 to similar to 2, the final mean size of the particles formed varies by a factor of 7, while subsequent increases in the ratio hardly have any effect on the size. In this paper, a model is developed to explain this widely varying dependence. The steps that lead to the formation of particles are as follows: reduction of Au3+ in solution, disproportionation of Au+ to gold atoms and their nucleation, growth by disproportionation on particle surface, and coagulation. Oxidation of citrate results in the formation of dicarboxy acetone, which aids nucleation but also decomposes into side products. A detailed kinetic model is developed on the basis of these steps and is combined with population balance to predict particle-size distribution. The model shows that, unlike the usual balance between nucleation and growth that determines the particle size, it is the balance between rate of nucleation and degradation of dicarboxy acetone that determines the particle size in the citrate process. It is this feature that is able to explain the unusual dependence of the mean particle size on the ratio of citrate to gold salt concentration. It is also found that coagulation plays an important role in determining the particle size at high concentrations of citrate.

Modeling of precipitation in reverse micellar systems

A model of the precipitation process in reverse micelles has been developed to calculate the size of fine particles obtained therein. While the method shares several features of particle nucleation and growth common to precipitation in large systems, complexities arise in describing the processes of nucleation, due to the extremely small size of a micelle and of particle growth caused by fusion among the micelles. Occupancy of micelles by solubilized molecules is governed by Poisson statistics, implying most of them are empty and cannot nucleate of its own. The model therefore specifies the minimum number of solubilized molecules required to form a nucleus which is used to calculate the homogeneous nucleation rate. Simultaneously, interaction between micelles is assumed to occur by Brownian collision and instantaneous fusion. Analysis of time scales of various events shows growth of particles to be very fast compared to other phenomena occurring. This implies that nonempty micelles either are supersaturated or contain a single precipitated particle and allows application of deterministic population balance equations to describe the evolution of the system with time. The model successfully predicts the experimental measurements of Kandori ct al.(3) on the size of precipitated CaCO3 particles, obtained by carbonation of reverse micelles containing aqueous Ca(OH)(2) solution.

Defining plausible migration rates based on historical tagging data: a Bayesian mark-recapture model applied to English sole (Parophrys vetulus)

A generalized Bayesian population dynamics model was developed for analysis of historical mark-recapture studies. The Bayesian approach builds upon existing maximum likelihood methods and is useful when substantial uncertainties exist in the data or little information is available about auxiliary parameters such as tag loss and reporting rates. Movement rates are obtained through Markov-chain Monte-Carlo (MCMC) simulation, which are suitable for use as input in subsequent stock assessment analysis. The mark-recapture model was applied to English sole (Parophrys vetulus) off the west coast of the United States and Canada and migration rates were estimated to be 2% per month to the north and 4% per month to the south. These posterior parameter distributions and the Bayesian framework for comparing hypotheses can guide fishery scientists in structuring the spatial and temporal complexity of future analyses of this kind. This approach could be easily generalized for application to other species and more data-rich fishery analyses.

Modeling the effect of striped bass (Morone saxatilis) on the population viability of Sacramento River winter-run chinook salmon (Onchorhynchus tshawytscha)

We estimated the impact of striped bass (Morone saxatilis) predation on winter-run chinook salmon (Oncorhynchus tshawytscha) with a Bayesian population dynamics model using striped bass and winter-run chinook salmon population abundance data. Winter-run chinook salmon extinction and recovery probabilities under different future striped bass abundance levels were estimated by simulating from the posterior distribution of model parameters. The model predicts that if the striped bass population declines to 512,000 adults as expected in the absence of stocking, winter-run chinook salmon will have about a 28% chance of quasi-extinction (defined as three consecutive spawning runs of fewer than 200 adults) within 50 years. If stocking stabilizes the striped bass population at 700,000 adults, the predicted quasi-extinction probability is 30%. A more ambitious stocking program that maintains a population of 3 million adult striped bass would increase the predicted quasi-extinction probability to 55%. Extinction probability, but not recovery probability, was fairly insensitive to assumptions about density dependence. We conclude that winter-run chinook salmon face a serious extinction risk without augmentation of the striped bass population and that substantial increases in striped bass abundance could significantly increase the threat to winter-run chi-nook salmon if not mitigated by increasing winter chinook salmon survival in some other way.

A stable carbon isotopic approach for understanding the CO2 flux at the Haibei Alpine Meadow Ecosystem - A simple model

Although respiration of organisms and biomass as well as fossil fuel burning industrial production are identified as the major sources, the CO2 flux is still unclear due to the lack of proper measurements. A mass-balance approach that exploits differences in the carbon isotopic signature (delta(13)C) of CO2 Sources and sinks was introduced and may provide a means of reducing uncertainties in the atmospheric budget. delta(13)C measurements of atmospheric CO2 yielded an average of - 10.3 parts per thousand relative to the Peedee Belemnite standard; soil and plants had a narrow range from -25.09 parts per thousand to -26.51 parts per thousand and averaged at -25.80 parts per thousand. Based on the fact of steady fractionation and enrichment during respiration of mitochondria, we obtained the emission Of CO2 of 35.451 mol m(-2) a(-1) and CO2 flux of 0.2149 mu mol m(-2) s(-)1. The positive CO2 flux indicated the Haibei Alpine Meadow Ecosystem a source rather than a sink. The mass-balance model can be applied for other ecosystem even global carbon cycles because it neglects the complicated process of carbon metabolism, however just focuses on stable carbon isotopic compositions in any of compartments of carbon sources and sinks. (C) 2005 Elsevier B.V. All rights reserved.

The impact of host immune status on the within-host and population dynamics of antigenic immune escape.

Antigenically evolving pathogens such as influenza viruses are difficult to control owing to their ability to evade host immunity by producing immune escape variants. Experimental studies have repeatedly demonstrated that viral immune escape variants emerge more often from immunized hosts than from naive hosts. This empirical relationship between host immune status and within-host immune escape is not fully understood theoretically, nor has its impact on antigenic evolution at the population level been evaluated. Here, we show that this relationship can be understood as a trade-off between the probability that a new antigenic variant is produced and the level of viraemia it reaches within a host. Scaling up this intra-host level trade-off to a simple population level model, we obtain a distribution for variant persistence times that is consistent with influenza A/H3N2 antigenic variant data. At the within-host level, our results show that target cell limitation, or a functional equivalent, provides a parsimonious explanation for how host immune status drives the generation of immune escape mutants. At the population level, our analysis also offers an alternative explanation for the observed tempo of antigenic evolution, namely that the production rate of immune escape variants is driven by the accumulation of herd immunity. Overall, our results suggest that disease control strategies should be further assessed by considering the impact that increased immunity--through vaccination--has on the production of new antigenic variants.

Validación de un modelo de balance hidrológico versátil para maíz en condiciones de semiáridez

p.125-132

iMarNet: an ocean biogeochemistry model intercomparison project within a common physical ocean modelling framework

Ocean biogeochemistry (OBGC) models span a wide variety of complexities, including highly simplified nutrient-restoring schemes, nutrient–phytoplankton–zooplankton–detritus (NPZD) models that crudely represent the marine biota, models that represent a broader trophic structure by grouping organisms as plankton functional types (PFTs) based on their biogeochemical role (dynamic green ocean models) and ecosystem models that group organisms by ecological function and trait. OBGC models are now integral components of Earth system models (ESMs), but they compete for computing resources with higher resolution dynamical setups and with other components such as atmospheric chemistry and terrestrial vegetation schemes. As such, the choice of OBGC in ESMs needs to balance model complexity and realism alongside relative computing cost. Here we present an intercomparison of six OBGC models that were candidates for implementation within the next UK Earth system model (UKESM1). The models cover a large range of biological complexity (from 7 to 57 tracers) but all include representations of at least the nitrogen, carbon, alkalinity and oxygen cycles. Each OBGC model was coupled to the ocean general circulation model Nucleus for European Modelling of the Ocean (NEMO) and results from physically identical hindcast simulations were compared. Model skill was evaluated for biogeochemical metrics of global-scale bulk properties using conventional statistical techniques. The computing cost of each model was also measured in standardised tests run at two resource levels. No model is shown to consistently outperform all other models across all metrics. Nonetheless, the simpler models are broadly closer to observations across a number of fields and thus offer a high-efficiency option for ESMs that prioritise high-resolution climate dynamics. However, simpler models provide limited insight into more complex marine biogeochemical processes and ecosystem pathways, and a parallel approach of low-resolution climate dynamics and high-complexity biogeochemistry is desirable in order to provide additional insights into biogeochemistry–climate interactions.

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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot 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. center dot 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 center dot 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. center dot 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. center dot 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. 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. 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. 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

The Effect of Volume Shape Factor on the Crystal Size Distribution of Fragments due to Attrition

The effect of volume shape factor on crystal size distribution (CSD) is usually ignored to simplify the analysis of population balance equation. In the present work, the CSD of fragments generated from a mechanically stirred crystallizer as the result of attrition mechanism has been reported when the volume shape factor conforms to normal distribution. The physical model of GAHN and MERSMANN which relates the attrition resistance of a crystalline substances to its mechanical properties has been employed. The simulation of fragment size distribution was performed by Monte Carlo (MC) technique. The results are compared with those reported by GAHN and MERSMANN.

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×(Weight /13.2)^0.75×EXP(-0.00158×TPT)×EXP(0.428×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 kg (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. © 2013 The British Pharmacological Society.

Optimisation de l’administration des médicaments chez les enfants transplantés grâce à la pharmacocinétique de population

Ce travail de thèse porte sur l’application de la pharmacocinétique de population dans le but d’optimiser l’utilisation de certains médicaments chez les enfants immunosupprimés et subissant une greffe. Parmi les différents médicaments utilisés chez les enfants immunosupprimés, l’utilisation du busulfan, du tacrolimus et du voriconazole reste problématique, notamment à cause d’une très grande variabilité interindividuelle de leur pharmacocinétique rendant nécessaire l’individualisation des doses par le suivi thérapeutique pharmacologique. De plus, ces médicaments n’ont pas fait l’objet d’études chez les enfants et les doses sont adaptées à partir des adultes. Cette dernière pratique ne prend pas en compte les particularités pharmacologiques qui caractérisent l’enfant tout au long de son développement et rend illusoire l’extrapolation aux enfants des données acquises chez les adultes. Les travaux effectués dans le cadre de cette thèse ont étudié successivement la pharmacocinétique du busulfan, du voriconazole et du tacrolimus par une approche de population en une étape (modèles non-linéaires à effets mixtes). Ces modèles ont permis d’identifier les principales sources de variabilités interindividuelles sur les paramètres pharmacocinétiques. Les covariables identifiées sont la surface corporelle et le poids. Ces résultats confirment l’importance de tenir en compte l’effet de la croissance en pédiatrie. Ces paramètres ont été inclus de façon allométrique dans les modèles. Cette approche permet de séparer l’effet de la mesure anthropométrique d’autres covariables et permet la comparaison des paramètres pharmacocinétiques en pédiatrie avec ceux des adultes. La prise en compte de ces covariables explicatives devrait permettre d’améliorer la prise en charge a priori des patients. Ces modèles développés ont été évalués pour confirmer leur stabilité, leur performance de simulation et leur capacité à répondre aux objectifs initiaux de la modélisation. Dans le cas du busulfan, le modèle validé a été utilisé pour proposer par simulation une posologie qui améliorerait l’atteinte de l’exposition cible, diminuerait l’échec thérapeutique et les risques de toxicité. Le modèle développé pour le voriconazole, a permis de confirmer la grande variabilité interindividuelle dans sa pharmacocinétique chez les enfants immunosupprimés. Le nombre limité de patients n’a pas permis d’identifier des covariables expliquant cette variabilité. Sur la base du modèle de pharmacocinétique de population du tacrolimus, un estimateur Bayesien a été mis au point, qui est le premier dans cette population de transplantés hépatiques pédiatriques. Cet estimateur permet de prédire les paramètres pharmacocinétiques et l’exposition individuelle au tacrolimus sur la base d’un nombre limité de prélèvements. En conclusion, les travaux de cette thèse ont permis d’appliquer la pharmacocinétique de population en pédiatrie pour explorer les caractéristiques propres à cette population, de décrire la variabilité pharmacocinétique des médicaments utilisés chez les enfants immunosupprimés, en vue de l’individualisation du traitement. Les outils pharmacocinétiques développés s’inscrivent dans une démarche visant à diminuer le taux d'échec thérapeutique et l’incidence des effets indésirables ou toxiques chez les enfants immunosupprimés suite à une transplantation.

Population Assessment of an Endangered Shorebird: the Piping Plover (Charadrius melodus melodus) in Eastern Canada

Small, at-risk populations are those for which accurate demographic information is most crucial to conservation and recovery, but also where data collection is constrained by logistical challenges and small sample sizes. Migratory animals in particular may experience a wide range of threats to survival and reproduction throughout each annual cycle, and identification of life stages most critical to persistence may be especially difficult for these populations. The endangered eastern Canadian breeding population of Piping Plover (Charadrius melodus melodus) was estimated at only 444 adults in 2005, and extensive effort has been invested in conservation activities, reproductive monitoring, and marking of individual birds, providing a comprehensive data set on population dynamics since 1998. We used these data to build a matrix projection model for two Piping Plover population segments that nest in eastern Canada in order to estimate both deterministic and stochastic rates of population growth (λd and λs, respectively). Annual population censuses suggested moderate growth in abundance between 1998–2003, but vital rate estimates indicated that this temporary growth may be replaced by declines in the long term, both in southern Nova Scotia (λd = 1.0043, λs = 0.9263) and in the Gulf of St. Lawrence (λd = 0.9651, λs = 0.8214). Nonetheless, confidence intervals on λ estimates were relatively wide, highlighting remaining uncertainty in future population trajectories. Differences in projected growth between regions appear to be driven by low estimated juvenile post-fledging survival in the Gulf, but threats to juveniles of both population segments following departure from nesting beaches remain unidentified. Similarly, λ in both population segments was particularly sensitive to changes in adult survival as expected for most migratory birds, but very little is understood about the threats to Piping Plover survival during migration and overwintering. Consequently, we suggest that future recovery efforts for these and other vulnerable migrants should quantify and manage the largely unknown sources of both adult and juvenile mortality during non-breeding seasons while maintaining current levels of nesting habitat protection.

How many facets are needed to represent the surface energy balance of an urban area?

We investigate the question of how many facets are needed to represent the energy balance of an urban area by developing simplified 3-, 2- and 1-facet versions of a 4-facet energy balance model of two-dimensional streets and buildings. The 3-facet model simplifies the 4-facet model by averaging over the canyon orientation, which results in similar net shortwave and longwave balances for both wall facets, but maintains the asymmetry in the heat fluxes within the street canyon. For the 2-facet model, on the assumption that the wall and road temperatures are equal, the road and wall facets can be combined mathematically into a single street-canyon facet with effective values of the heat transfer coefficient, albedo, emissivity and thermodynamic properties, without further approximation. The 1-facet model requires the additional assumption that the roof temperature is also equal to the road and wall temperatures. Idealised simulations show that the geometry and material properties of the walls and road lead to a large heat capacity of the combined street canyon, whereas the roof behaves like a flat surface with low heat capacity. This means that the magnitude of the diurnal temperature variation of the street-canyon facets are broadly similar and much smaller than the diurnal temperature variation of the roof facets. Consequently, the approximation that the street-canyon facets have similar temperatures is sound, and the road and walls can be combined into a single facet. The roof behaves very differently and a separate roof facet is required. Consequently, the 2-facet model performs similarly to the 4-facet model, while the 1-facet model does not. The models are compared with previously published observations collected in Mexico City. Although the 3- and 2-facet models perform better than the 1-facet model, the present models are unable to represent the phase of the sensible heat flux. This result is consistent with previous model comparisons, and we argue that this feature of the data cannot be produced by a single column model. We conclude that a 2-facet model is necessary, and for numerical weather prediction sufficient, to model an urban surface, and that this conclusion is robust and therefore applicable to more general geometries.