William Couet

Université de Poitiers, Poitiers, Poitou-Charentes, France

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Publications (106)403.34 Total impact

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    ABSTRACT: Background: Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration. Methods: Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters. Results: Following intravenous administration, the clearance and central compartment (Vc) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT Vc after IT administration and the EPI Vc after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively. Conclusions: Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.
    Regional anesthesia and pain medicine 10/2015; 40(6). DOI:10.1097/AAP.0000000000000322 · 3.09 Impact Factor
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    ABSTRACT: The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star® than the Eflow rapid® system. A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star® than with the Eflow Rapid® system.
    Pharmaceutical Research 06/2015; 32(10). DOI:10.1007/s11095-015-1716-0 · 3.42 Impact Factor
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    ABSTRACT: We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the different components occurring during the spray drying process and to obtain homogeneous LPPs, spray drying parameters were modified to decrease the drying speed. As a result, good aerodynamic properties for lung delivery were obtained with a fine particle fraction (FPF) of 40.1 ± 1.0 % and an alveolar fraction (AF) of 29.6 ±3.1 %, a mass median aerodynamic diameter (MMADaer) of 4.1 ± 0.2 μm and a geometric standard deviation (GSD) of 2.16 ± 0.16. Plasma and epithelial lining fluid (ELF) concentrations of pyrazinamide were evaluated after intratracheal insufflation of PZA-LPPs (4.22 mg.kg(-1)) into rats and compared to intravenous administration (iv) of a pyrazinamide solution (5.82 mg.kg(-1)). The in vivo pharmacokinetic evaluation of PZA-LPPs in rats reveals that intratracheal insufflation of PZA-LPPs leads to a rapid absorption in plasma with an absolute bioavailability of 66%. This proves that PZA-LPPs dissolve fast upon deposition and that PZA crosses efficiently the lung barrier to reach the systemic circulation. PZA concentrations were 1.28-fold higher in ELF after intratracheal administration than after iv administration and the ratio of ELF concentrations over plasma concentrations was 2-fold greater. Although these improvements are moderate, lung delivery of PZA appears an interesting alternative to oral delivery of the molecule and should now be tested in an infected animal model to evaluate its efficacy against Mycobacterium tuberculosis. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 05/2015; 94. DOI:10.1016/j.ejpb.2015.05.021 · 3.38 Impact Factor
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    ABSTRACT: In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, dinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymuxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.
    The Lancet Infectious Diseases 02/2015; 15(2):225-234. DOI:10.1016/S1473-3099(14)70850-3 · 22.43 Impact Factor
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    ABSTRACT: Colistin is a last resort's antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid – BEH – Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006 μg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6–8.4%) and accurate (intra-/inter-assay deviation from nominal concentrations −4.4 to +6.3%) over the clinically relevant analytical range 0.05–20 μg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48 h at room temperature and at +4 °C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1 M H2SO4) to colistin A and B in plasma was completed in vitro after 15 min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4 h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real-life conditions of the microbiologically active compounds colistin A and B offers a highly efficient tool for routine therapeutic drug monitoring aimed at individualizing drug dosing against life-threatening infections.
    Journal of Chromatography A 11/2014; 1369. DOI:10.1016/j.chroma.2014.09.063 · 4.17 Impact Factor
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    ABSTRACT: Colistin is an old antibiotic that has recently gained a considerable renew of interest for the treatment of pulmonary infections due to Multi Drug Resistant Gram-negative bacteria. Nebulization seems promising for this application but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS), but differences between intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients, have not been precisely documented. CMS and colistin concentrations were measured on two separate occasions within plasma and epithelial lining fluid (ELF) of critically ill patients (n=12) who had received 2 MIU of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic(PK-PD) modelling and simulations. ELF colistin concentrations varied considerably (9.53 - 1137 mg/L) but were much higher than in plasma (0.15 - 0.73 mg/L) after aerosol delivery, but not after intravenous administrationof CMS.Following CMS aerosol delivery, typically 9% of the CMS dose reached the ELF, and only 1.4 % was converted into colistin pre-systemically. PK-PD analysis concluded to a much higher antimicrobial efficacy after CMS aerosol delivery than intravenous administration. These new data seem to support the use of CMS aerosol delivery for the treatment of pulmonary infections in critical care patients.
    Antimicrobial Agents and Chemotherapy 09/2014; 58(12). DOI:10.1128/AAC.03510-14 · 4.48 Impact Factor
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    ABSTRACT: Colistin is an old antibiotic that has recently gained a considerable renew of interest as the last line defense therapy against Multi Drug Resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rational for a loading dose in critically ill patients. Yet faster CMS conversion was observed in healthy volunteers, but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics.
    Antimicrobial Agents and Chemotherapy 09/2014; 58(12). DOI:10.1128/AAC.03508-14 · 4.48 Impact Factor

  • Annales Françaises d Anesthésie et de Réanimation 09/2014; 33:A221-A222. DOI:10.1016/j.annfar.2014.07.372 · 0.84 Impact Factor
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    ABSTRACT: The aim of this study was to determine biopharmaceutical charcateristics of tobramycin (TOB) after nebulization in rats. TOB was administered by intravenous (IV) bolus and intra-tracheal nebulization (3mg.kg(-1)) and concentrations were determined in plasma and epithelial lining fluid (ELF) by LC-MS/MS. TOB ELF over plasma area under the curve (AUC) ratio was more than 200 times higher after NEB than after IV bolus indicating that TOB nebulisation offers a biopharmaceutical advantage compared to IV administration. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(7). DOI:10.1128/AAC.02819-14 · 4.48 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs): ciprofloxacin (CIP), moxifloxacin (MXF) and grepafloxacin (GRX) after nebulization in rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4 and 6h after FQ intravenous administration and nebulization to estimate epithelial lining fluid (ELF) concentrations. Plasma concentrations were also measured and profiles of concentrations versus time after intravenous administration and nebulization were virtually superimposed, attesting for rapid and complete systemic absorption of FQs. ELF concentrations were systematically higher than corresponding plasma concentrations whatever the administration and averaged ELF to unbound plasma concentration ratios at post distribution equilibrium did not change significantly between the ways of administration, and were equal to 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF and 19.1 ± 10.5 for GRX. The impact of macrophage lysis on estimated ELF concentrations was significant for GRX, but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF concentrations was only performed for the latter two drugs.The model was characterized by a fixed volume of ELF (VELF), a passive diffusion clearance (QELF) and an active efflux clearance (CLout) between plasma and ELF characterizing active efflux transport systems. In conclusion, this study has demonstrated that ELF concentrations of these three FQs are several times higher than plasma concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level but no biopharmaceutical advantage of FQ nebulization was observed compared with IV.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(7). DOI:10.1128/AAC.02818-14 · 4.48 Impact Factor
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    ABSTRACT: The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0–τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml−1. This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.
    Antimicrobial Agents and Chemotherapy 02/2014; 58(2). DOI:10.1128/AAC.01760-13 · 4.48 Impact Factor
  • F Tewes · J Brillault · JC Olivier · W Couet ·

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    ABSTRACT: This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification-evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10 h and maintained for 48 h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller(®) pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 12/2013; 86(2). DOI:10.1016/j.ejpb.2013.12.004 · 3.38 Impact Factor
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    ABSTRACT: This study explored CSF metronidazole and hydroxy-metronidazole distribution in brain-injured patients.Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8h. CSF and blood samples were collected at steady-state over 8 h and metronidazole and hydroxy-metronidazole concentrations were assayed by HPLC. A non-compartmental analysis was performed.Metronidazole distributes extensively within CSF with a mean CSF over unbound plasma AUC0-τ ratio equal to 86 ± 16 %. Yet concentrations profiles in CSF were mostly flat compared with plasma profiles. Hydroxy-metronidazole concentrations were much lower than those of metronidazole both in plasma and CSF with a corresponding CSF over unbound plasma AUC0-τ ratio equal to 79 ± 16 %.This study was the first one to describe in details the pharmacokinetics of metronidazole and hydroxy -metronidazole in CSF.
    Antimicrobial Agents and Chemotherapy 11/2013; 58(2). DOI:10.1128/AAC.01762-13 · 4.48 Impact Factor

  • Clinical Infectious Diseases 10/2013; 58(1). DOI:10.1093/cid/cit680 · 8.89 Impact Factor

  • Annales Françaises d Anesthésie et de Réanimation 09/2013; 32:A248-A249. DOI:10.1016/j.annfar.2013.07.465 · 0.84 Impact Factor
  • M. Boisson · N. Grégoire · W. Couet · B. Debaene · O. Mimoz ·

    Annales Françaises d Anesthésie et de Réanimation 09/2013; 32:A75-A76. DOI:10.1016/j.annfar.2013.07.154 · 0.84 Impact Factor

  • Annales Françaises d Anesthésie et de Réanimation 09/2013; 32:A248-A249. · 0.84 Impact Factor
  • M. Boisson · N. Gregoire · W. Couet · B. Debaene · O. Mimoz ·

    Annales Françaises d Anesthésie et de Réanimation 09/2013; 32:A75-A76. · 0.84 Impact Factor
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    ABSTRACT: Hypovolemia is a common event in critical care patients that may affect drug distribution and elimination. In order to better understand this issue the effect of hypovolemia on the plasma protein binding and tissue distribution of ertapenem was investigated in rats using microdialysis. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Ertapenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced in 6 rats by removing 40% of the initial blood volume over 30 min. Ertapenem was infused intravenously at a dose of 40 mg,kg(-1) over 30 min, and microdialysis samples were collected for 310 min. The unbound concentration profiles in muscle and blood were virtually superimposed in both groups except at early time points. The ratios of the area under the concentration-time curve (AUC) for tissue to the AUC for blood were 0.7± 0.2 and 0.8 ± 0.2 for control and hypovolemic rats, respectively. Hypovolemia induced a 40% decrease in the clearance of ertapenem, with no statistically significant alteration of its volume of distribution. This study showed that ertapenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. Unbound concentrations of ertapenem in blood and muscle were always virtually identical.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 08/2013; 51(1). DOI:10.1016/j.ejps.2013.08.017 · 3.35 Impact Factor

Publication Stats

2k Citations
403.34 Total Impact Points


  • 2006-2015
    • Université de Poitiers
      Poitiers, Poitou-Charentes, France
    • The University of Manchester
      Manchester, England, United Kingdom
    • Centre Hospitalier Universitaire de Poitiers
      Poitiers, Poitou-Charentes, France
  • 2012-2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • University of Cambridge
      Cambridge, England, United Kingdom