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

A Kinetic Database For Astrochemistry (KIDA)

We present a novel chemical database for gas-phase astrochemistry. Named the KInetic Database for Astrochemistry (KIDA), this database consists of gas-phase reactions with rate coefficients and uncertainties that will be vetted to the greatest extent possible. Submissions of measured and calculated rate coefficients are welcome, and will be studied by experts before inclusion into the database. Besides providing kinetic information for the interstellar medium, KIDA is planned to contain such data for planetary atmospheres and for circumstellar envelopes. Each year, a subset of the reactions in the database (kida.uva) will be provided as a network for the simulation of the chemistry of dense interstellar clouds with temperatures between 10 K and 300 K. We also provide a code, named Nahoon, to study the time-dependent gas-phase chemistry of zero-dimensional and one-dimensional interstellar sources

Optimal control of a Cope rearrangement by coupling the reaction path to a dissipative bath or a second active mode

International audienc

Modeling restoration of gefitinib efficacy by co-administration of MET inhibitors in an EGFR inhibitor-resistant NSCLC xenograft model: A tumor-in-host DEB-based approach

MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor‐in‐host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly‐targeted combination therapies. The population DEB‐based tumor growth inhibition (TGI) model well‐described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib‐resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB‐TGI model allowed to capture gefitinib anticancer activity enhanced by the co‐administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model‐based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB‐based tumor‐in‐host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor‐in‐host DEB‐TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies

Cultural adaptation and validation of patient decision aids: a scoping review

Vanessa Chenel,1,2 W Ben Mortenson,3–5 Manon Guay,6,7 Jeffrey William Jutai,8,9 Claudine Auger1,2 1School of Rehabilitation, Faculty of Medicine, Université de Montréal, 2Centre for Interdisciplinary Research in Rehabilitation of Greater Montreal (CRIR) – Institut universitaire sur la réadaptation en déficience physique de Montréal, Centre intégré universitaire de santé et de services sociaux du Centre-Sud-de-l’Île-de-Montréal, Montreal, QC, 3Department of Occupational Science and Occupational Therapy, Faculty of Medicine, University of British Columbia, 4GF Strong Rehabilitation Centre, 5International Collaboration on Repair Discoveries, University of British Columbia, Vancouver Coastal Health Research Institute, Vancouver, BC, 6School of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 7Research Centre on Aging, Centre intégré universitaire de santé et de services sociaux de l’Estrie – Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, 8Interdisciplinary School of Health Sciences, University of Ottawa, 9Bruyère Research Institute, Ottawa, ON, Canada Abstract: In order to promote self-determination, patients have to be actively involved with their care providers in health-care decision making, especially when such decisions involve personal preferences. Decision aids (DAs) are tools that can contribute to patient-centered decision-making processes. To benefit from previous fieldwork and avoid duplicating developmental efforts and producing many similar DAs, the adaptation of existing DAs to new cultural contexts is a resource-saving option. However, there are no guidelines on how to culturally adapt and validate DAs. This study aimed to identify and document existing procedures for the cultural adaptation and validation of patient DAs. A scoping review examined studies conducting cultural adaptation and/or validation of patient DAs. The following databases were searched in February 2016: CINAHL, EMBASE, Medline (Ovid), PASCAL, PsychINFO, and PubMed. From the 13 studies selected, 11 main procedures were identified: appraisal of the original DA, assessment of the new cultural context, translation, linguistic adaptation, cultural adaptation, usability testing, exploration of DA acceptability, test-retest reliability, content validity, con­struct validity, and criterion validity. A conceptual synthesis of these studies suggests there are four phases in the adaptation/validation process of DAs aimed at: 1) exploring the original DA and the new cultural context, 2) adapting the original DA to the new cultural context, 3) lab testing the preliminary version of the adapted DA, and 4) field testing the adapted DA in a real use context. By facilitating the adaptation and broader implementation of DAs, patients may ultimately be empowered in decision-making processes. Keywords: decision making, decision support techniques, translation, cultural adaptation, validation studie

Place du test de permutation dans les modèles non linéaires à effets mixtes : application en pharmacogénétique

International audienceLa pharmacocinétique étudie le devenir du médicament dans l'organisme. Pour certains médicaments il existe une forte variabilité interindividuelle qui peut être expliquée par des polymorphismes génétiques. Les modèles non linéaires à effets mixtes permettent de quantifier cette variabilité. Les principaux tests pour détecter l'existence d'un effet gène sur un paramètre pharmacocinétique dans ces modèles sont i) un test de Wald sur les coefficients estimés par le modèle avec la covariable génétique et ii) un test du rapport de vraisemblance (LRT) entre les modèles avec et sans la covariable. Les données à l'origine de ce travail proviennent d'une sous-étude sur la pharmacocinétique de l'indinavir réalisée sur 40 patients dans l'essai COPHAR2-ANRS 111. Nous avons évalué le test de Wald et le LRT par une étude de simulation inspirée des données réelles en utilisant l'algorithme d'estimation exact SAEM. Une inflation de l'erreur de type I est observée pour les deux tests sur ce plan d'expérience. Nous avons alors évalué la correction par simulation et son alternative non-paramétrique : le test de permutation. Les deux approches permettent de ramener l'erreur de type I des deux tests à un seuil nominal de 5\%. Un effet du polymorphisme du CYP3A4*1B sur la constante d'absorption de l'indinavir est mis en évidence. Sur de petits échantillons avec des groupes déséquilibrés, on observe une inflation de l'erreur de type I des tests asymptotiques communément employés. La correction par permutation semble appropriée lorsque l'algorithme d'estimation ne pose pas de limites en termes de convergence et/ou de temps de calcul

The acceptability of nanocarriers for drug delivery in different contexts of use: perceptions of researchers and research trainees in the field of new technologies

International audienceBackground: Despite marked optimism in the field of nanomedicine about the use of drug-delivery nanocarriers, uncertainties exist concerning nanocarriers’ possible unintended impacts and effects. These uncertainties could affect user acceptance and acceptability. “Acceptance” refers to the intention to put a technology or a device to a specified use. “Acceptability” refers to a value judgment that accounts for acceptance. The objectives of this study were to characterize impact perception, acceptance, and acceptability in relation to drug-delivery nanocarriers in different contexts of use, and to explore relationships among these concepts. Methods: A sample of European and Canadian researchers and graduate research trainees active in the field of new technologies was recruited by targeted email invitation for participation in a web-based questionnaire study. The questionnaire presented scenarios for two contexts of use (lung cancer, seasonal flu) of drug-delivery nanocarriers with two compositions (carbon, synthetic DNA). Respondents’ impact perception, acceptance, and acceptability judgment in relation to each kind of nanocarrier in each context of use were measured with Likert scale questions and scored using categorical values. Results: Two hundred and fourteen researchers and graduate research trainees completed the questionnaire. The results showed that nanocarrier composition influenced impact perception: as compared with the carbon nanocarrier impact perception, the positive impacts of the synthetic DNA nanocarrier were perceived as more significant and more likely to occur than its negative impacts. Composition did not influence acceptance or acceptability. Context of use significantly influenced acceptance and acceptability of both kinds of nanocarriers: researchers were more likely to accept the use of nanocarriers to treat lung cancer than the seasonal flu. The results also showed a significant relationship between acceptance and the perceived usefulness of the treatments. Conclusion: Nanocarrier composition does not appear to influence acceptance or acceptability. On the other hand, the nanocarriers’ perceived usefulness and context of use are both major factors in accounting for acceptance and acceptability. Keywords: acceptance, impact perception, nanomedicine, researchers’ perceptions, ELSI, E3L

Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm.

The original publication is available at www.springerlink.comInternational audiencePharmacogenetics is now widely investigated and health institutions acknowledge its place in clinical pharmacokinetics. Our objective is to assess through a simulation study, the impact of design on the statistical performances of three different tests used for analysis of pharmacogenetic information with nonlinear mixed effects models: (i) an ANOVA to test the relationship between the empirical Bayes estimates of the model parameter of interest and the genetic covariate, (ii) a global Wald test to assess whether estimates for the gene effect are significant, and (iii) a likelihood ratio test (LRT) between the model with and without the genetic covariate. We use the stochastic EM algorithm (SAEM) implemented in MONOLIX 2.1 software. The simulation setting is inspired from a real pharmacokinetic study. We investigate four designs with N the number of subjects and n the number of samples per subject: (i) N = 40/n = 4, similar to the original study, (ii) N = 80/n = 2 sorted in 4 groups, a design optimized using the PFIM software, (iii) a combined design, N = 20/n = 4 plus N = 80 with only a trough concentration and (iv) N = 200/n = 4, to approach asymptotic conditions. We find that the ANOVA has a correct type I error estimate regardless of design, however the sparser design was optimized. The type I error of the Wald test and LRT are moderatly inflated in the designs far from the asymptotic (<10%). For each design, the corrected power is analogous for the three tests. Among the three designs with a total of 160 observations, the design N = 80/n = 2 optimized with PFIM provides both the lowest standard error on the effect coefficients and the best power for the Wald test and the LRT while a high shrinkage decreases the power of the ANOVA. In conclusion, a correction method should be used for model-based tests in pharmacogenetic studies with reduced sample size and/or sparse sampling and, for the same amount of samples, some designs have better power than others

Discrepancies in phylogeographical patterns of two european anglefishes (Lophius budegassa and Lophius piscatorius

International audienceIn order to investigate the relative importance of historical processes and life-history traits in shaping the present-day genetic structure of European anglerfishes, 382 Lophius piscatorius and 134 Lophius budegassa were sequenced on the 5' end of the mitochondrial control region. Both species showed a limited genetic structure and some evidence of a demographic expansion that probably occurred not at the end of the Last Glacial Maximum, but earlier in the Pleistocene. The main discrepancy between the two anglerfishes concerned the genetic structure between Atlantic and Mediterranean populations, with weak but significant differentiation observed only in L. budegassa. This genetic structure was congruent with the existence of a phylogeographical break previously reported in several marine species across the Almeria-Oran front. The contrast observed between both anglerfishes was supposed to be induced by a possible more ancient (re)colonisation of the Mediterranean Sea by L. budegassa. Finally, the limited genetic structure and lack of isolation by distance observed in both species suggested high larval dispersal capacities that probably overwhelm the influence of the bathymetric distribution range on migrations of adults and juveniles