Pharmacocinétique clinique de l'ilopéridone injectable à action prolongée chez les patients atteints de schizophrénie

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude de la variabilité pharmacocinétique de l'emtricitabine chez l'adulte infecté par le VIH, par une approche de population

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude de l'effet de traitements antirétroviraux sur la perméabilité de la barrière hémato-encéphalique chez le rat soumis à inflammation

PARIS-BIUP (751062107) / SudocSudocFranceF

Evaluation de l'activité et de l'expression des transporteurs hépatiques OATP1B1 et OATP1B3 (application de facteurs d'extrapolation aux simulations PBPK)

PARIS-BIUP (751062107) / SudocSudocFranceF

Microsphères synthétiques de type poly(esters) injectables (biopharmacie et modélisation pharmacocinétique)

PARIS-BIUP (751062107) / SudocSudocFranceF

Implication des transporteurs d'influx et d'efflux dans la neuropharmacocinétique des xénobiotiques

PARIS-BIUP (751062107) / SudocSudocFranceF

Carrier-mediated processes at several rat brain interfaces determine the neuropharmacokinetics of morphine and morphine-6-beta-D-glucuronide.

International audienceWe investigated whether capacity-limited transport processes were involved in morphine and morphine-6-beta-D-glucuronide (M6G) neuropharmacokinetics, at the level of the blood-brain barrier (BBB), the brain extra- and intra-cellular fluids (bECF/bICF), and the bECF/cerebrospinal fluid (CSF) interfaces. We performed transcortical retrodialysis in the rat, by perfusing morphine or M6G through the microdialysis probe in the presence or absence of probenecid. We measured for each compound the in vitro and in vivo (R(D)) probe recoveries. The in vivo R(D), which takes into account the permeability of the tissue surrounding the probe, informs about the morphine and M6G distribution capabilities from bECF to adjacent fluids (bICF, CSF, plasma). We also measured plasma and CSF concentrations at three time points after having added probenecid or not. Finally, we tested several pharmacokinetic models, assuming first-order or capacity-limited processes at each brain interface, to describe experimental morphine and M6G concentrations previously obtained in rat plasma and brain fluids. We found that morphine distributes more easily outside bECF than M6G. Adding probenecid caused a 2-fold decrease and a 1.3-fold increase in morphine and M6G R(D), respectively, and 30 min after adding probenecid, plasma and CSF concentrations increased for M6G but not for morphine. The pharmacokinetic model that gave the best fit included capacity-limited processes at the BBB and bECF/bICF interface for morphine and at the BBB and bECF/CSF interface for M6G. In conclusion, morphine accumulates into brain cells thanks to a probenecid-sensitive transporter located at the bECF/bICF interface, whereas M6G is trapped in bECF thanks to transporters located at the BBB and the bECF/CSF interface

Epidemiokinetic Tools to Monitor Lockdown Efficacy and Estimate the Duration Adequate to Control SARS-CoV-2 Spread

International audienceVarious key performance indicators (KPIs) are communicated daily to the public by health authorities since the COVID-19 pandemic has started. “Upstream” KPIs mainly include the incidence of detected Sars-CoV-2-positive cases in the population, and “downstream” KPIs include daily hospitalizations, intensive care unit admissions and fatalities. Whereas “downstream” KPIs are essential to evaluate and adapt hospital organization, “upstream” KPIs are the most appropriate to decide on the strength of restrictions such as lockdown set up and evaluate their effectiveness. Here, we suggested tools derived from pharmacokinetic calculations to improve understanding the epidemic progression. From the time course of the number of new cases of SARS-coV-2 infection in the population, it is possible to calculate the infection rate constant using a simple linear regression and determine its corresponding half-life. This epidemic regression half-life is helpful to measure the potential benefits of restriction measures and to estimate the adequate duration of lockdown if implemented by policymakers in relation to the decided public health objectives. In France, during the first lockdown, we reported an epidemic half-life of 10 days. Our tools allow clearly acknowledging that the zero-COVID target is difficult to reach after a period of lockdown as seven half-lives are required to clear 99.2% of the epidemic and more than 10 half-lives to almost reach the objective of eliminating 100% of the contaminations

Is Curfew Effective in Limiting SARS-CoV-2 Progression? An Evaluation in France Based on Epidemiokinetic Analyses

International audienceBackground: Since late summer 2020, the French authorities implemented a curfew/lightened lockdown-alternating strategy instead of strict lockdown, to improve acceptability and limit socioeconomic consequences. However, data on curfew-related efficacy to control the epidemic are scarce.Objective: To investigate the effects on COVID-19 spread in France of curfew combined to local and/or nationwide restrictions from late summer 2020 to mid-February 2021.Design: We conducted a comparative evaluation using a susceptible-infected-recovered (SIR)-based model completed with epidemiokinetic tools.Main measures: We analyzed the time-course of epidemic progression rate under curfew in French Guyana and five metropolitan regions where additional restrictions were implemented at different times. Using linear regressions of the decay/increase rates in daily contaminations, we calculated the epidemic regression half-lives (t1/2β) for each identified period.Key results: In French Guyana, two decay periods with rapid regression (t1/2β of ~10 days) were observed under curfew, with slowing (t1/2β of ~43 days) when curfew was lightened. During the 2-week pre-lockdown curfew (2020/10/17-2020/11/02) in Provence-Alpes-Côte-d'Azur, Auvergne-Rhône-Alpes, and Ile-de-France, the epidemic progression was unchanged. During the post-lockdown curfew (2020/12/15-2020/02/14), the epidemic slowly regressed in Grand-Est (t1/2β of ~37 days), whereas its progression rate plateaued in Auvergne-Rhône-Alpes and increased immediately in Provence-Alpes-Côte-d'Azur, Ile-de-France, and Nouvelle-Aquitaine, whatever the curfew starting time was (06:00 or 08:00 pm). Interestingly, a delayed slow decay (17 days < t1/2β < 64 days) occurred under curfew in all regions except Ile-de-France.Conclusions: Curfew allowed the temporary control of SARS-CoV-2 epidemic, however variably in the French regions, without preventing lockdown necessity. To accelerate the epidemic regression such as observed in French Guyana, curfew should be implemented timely with additional restrictions

Is Lockdown Effective in Limiting SARS-CoV-2 Epidemic Progression?—a Cross-Country Comparative Evaluation Using Epidemiokinetic Tools

International audienceBackground: To date, the risk/benefit balance of lockdown in controlling severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemic is controversial.Objective: We aimed to investigate the effectiveness of lockdown on SARS-CoV-2 epidemic progression in nine different countries (New Zealand, France, Spain, Germany, the Netherlands, Italy, the UK, Sweden, and the USA).Design: We conducted a cross-country comparative evaluation using a susceptible-infected-recovered (SIR)-based model completed with pharmacokinetic approaches.Main measures: The rate of new daily SARS-CoV-2 cases in the nine countries was calculated from the World Health Organization's published data. Using a SIR-based model, we determined the infection (β) and recovery (γ) rate constants; their corresponding half-lives (t1/2β and t1/2γ); the basic reproduction numbers (R0 as β/γ); the rates of susceptible S(t), infected I(t), and recovered R(t) compartments; and the effectiveness of lockdown. Since this approach requires the epidemic termination to build the (I) compartment, we determined S(t) at an early epidemic stage using simple linear regressions.Key results: In New Zealand, France, Spain, Germany, the Netherlands, Italy, and the UK, early-onset stay-at-home orders and restrictions followed by gradual deconfinement allowed rapid reduction in SARS-CoV-2-infected individuals (t1/2β ≤ 14 days) with R0 ≤ 1.5 and rapid recovery (t1/2γ ≤ 18 days). By contrast, in Sweden (no lockdown) and the USA (heterogeneous state-dependent lockdown followed by abrupt deconfinement scenarios), a prolonged plateau of SARS-CoV-2-infected individuals (terminal t1/2β of 23 and 40 days, respectively) with elevated R0 (4.9 and 4.4, respectively) and non-ending recovery (terminal t1/2γ of 112 and 179 days, respectively) was observed.Conclusions: Early-onset lockdown with gradual deconfinement allowed shortening the SARS-CoV-2 epidemic and reducing contaminations. Lockdown should be considered as an effective public health intervention to halt epidemic progression