Publications by authors named "Yoann Cazaubon"

15 Publications

  • Page 1 of 1

Quantification of methadone, buprenorphine, naloxone, opioids, and their derivates in whole blood by liquid chromatography-high-resolution mass spectrometry: Analysis of their involvement in fatal forensic cases.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Sep 9;1152:122226. Epub 2020 Jun 9.

Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims Cedex, France. Electronic address:

Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone, buprenorphine…). When these products are misused, they are often addictive. Thus, we aimed to develop an analytical method able to rapidly quantify several opiates and opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, ethylmorphine, heroin, methadone, morphine, nalbuphine, naloxone, norbuprenorphine, norcodeine, norpropoxyphene, oxycodone and propoxyphene) in whole blood by ultra-high performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The validated assay requires only 100 µL of the blood sample. The sample is prepared by a rapid liquid-liquid extraction using 5% zinc sulfate (W/V), methanol and acetonitrile. Calibration curves range from 0.98 to 1000 µg/L, except for buprenorphine (0.39-100 µg/L) and norbuprenorphine (0.20-100 µg/L). Inter- and intra-analytical accuracy was less than 15%. Therefore, we describe the development and full validation of an accurate, sensitive and precise assay using UHPLC-HRMS for the analysis of opioids in whole blood. After validation, this new assay is successfully applied on a routine laboratory application basis.
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http://dx.doi.org/10.1016/j.jchromb.2020.122226DOI Listing
September 2020

Lactic Acidosis after Drinking Mysterious Beverage.

Clin Chem 2020 May;66(5):744-745

Laboratoire de Biochimie-Pharmacologie-Toxicologie, CHU de Reims, Reims, France.

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http://dx.doi.org/10.1093/clinchem/hvaa008DOI Listing
May 2020

Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics 2020 Apr 21;12(4). Epub 2020 Apr 21.

Department of Medical Pharmacology, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France.

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
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http://dx.doi.org/10.3390/pharmaceutics12040380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238177PMC
April 2020

Myocardial infarction in relation to colchicine poisoning: A precipitating cause of refractory toxic cardiogenic shock.

Therapie 2021 Jan-Feb;76(1):51-53. Epub 2020 Jan 13.

Department of medical and toxicological critical care, Lariboisière hospital, Paris-Diderot University, INSERM UMRS-1144, 75010 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.therap.2019.12.012DOI Listing
January 2020

Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics 2019 Oct 31;11(11). Epub 2019 Oct 31.

Department of Medical Pharmacology, EA3801, SFR Cap-Santé, Reims University Hospitals, 51100 Reims, France.

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2-3 g/day and should be slightly increased to reach the therapeutic index of 14-20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.
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http://dx.doi.org/10.3390/pharmaceutics11110566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920765PMC
October 2019

Complementary Role of P2 and Adenosine Receptors in ATP Induced-Anti-Apoptotic Effects Against Hypoxic Injury of HUVECs.

Int J Mol Sci 2019 Mar 22;20(6). Epub 2019 Mar 22.

Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims CEDEX, France.

Background: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury.

Methods: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors.

Results: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoK, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS.

Conclusions: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.
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http://dx.doi.org/10.3390/ijms20061446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470483PMC
March 2019

Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia.

Clin Pharmacokinet 2018 09;57(9):1135-1147

Department of Pharmacology, EA3801, SFR CAP-Santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095, Reims Cedex, France.

Background: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown.

Objective: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia.

Methods: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping.

Results: Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics.

Conclusions: This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight.

Study Registration: This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France).
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http://dx.doi.org/10.1007/s40262-017-0617-2DOI Listing
September 2018

Population pharmacokinetics of articaine with 1:200,000 epinephrine during third molar surgery and simulation of high-dose regimens.

Eur J Pharm Sci 2018 Mar 29;114:38-45. Epub 2017 Nov 29.

Department of Pharmacology and Toxicology, Pharmacology and Toxicology Laboratory, Reims University Hospital, 45 rue Cognacq Jay, Reims 51092, France; Department of Pharmacology, EA3801, SFR CAP-santé, URCA Reims University, Reims 51100, France. Electronic address:

Background And Objectives: Articaine is more and more used in third molar surgery under local anesthesia (LA). The objectives of this analysis were to characterize the pharmacokinetics of articaine for this type of surgery and to simulate dosing regimens.

Methods: Non-linear mixed-effects modeling conducted in Monolix 4.4.0 was used to describe articaine plasma concentration-time data from 20 patients. Monte Carlo simulations were then performed to evaluate the probability of cardiotoxic target attainment (PCTA) of various dosage regimens.

Results: Articaine concentration data were best described by a linear one-compartment model, with an additional depot compartment for submucosal route with a zero-order transfer to central compartment. Age and gender were found to influence duration transfer (Tk0) and elimination rate constant (Ke), respectively. Simulated maximum recommended dose regimen (7mg/kg) had a PCTA of 0%. Simulated higher doses of 10mg/kg and 15mg/kg had a PCTA of 0% and about 1-4%, respectively.

Conclusions: The model adequately described the articaine pharmacokinetics. This is the first PK model qualified for articaine administered by submucosal route. The simulations suggest that maximum recommended dose regimen is safe concerning the cardiotoxicity in healthy patients.
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http://dx.doi.org/10.1016/j.ejps.2017.11.027DOI Listing
March 2018

Population pharmacokinetics of teicoplanin administered by subcutaneous or intravenous route and simulation of optimal loading dose regimen.

J Antimicrob Chemother 2017 10;72(10):2804-2812

UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, CNRS, Claude Bernard Lyon 1 University, 43 bd du 11 novembre 1918, 69622 Villeurbanne, France.

Objectives: To investigate the population pharmacokinetics of teicoplanin in patients treated by the subcutaneous (sc) and/or intravenous (iv) route.

Patients And Methods: Non-linear mixed-effects modelling described teicoplanin concentrations from 98 patients with infection caused by Gram-positive cocci. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of various dosage regimens.

Results: Teicoplanin concentrations were best described by a two-compartment model with clearance predicted by estimated glomerular filtration rate. Estimated absorption rate constant (between-subject variability) was 0.039 h-1 (77%), clearance was 0.305 L/h (28%), central volume was 10.3 L (49%), inter-compartmental clearance was 4.42 L/h (66%) and peripheral volume was 97.4 L (51%). The sc route was associated with lower initial Cmin and AUC (day 3: loading phase) compared with the iv route. This difference appeared to vanish after 14 days, with comparable simulated PTAs based on the Cmin and AUC for all tested dosages (400, 600, 800 and 1000 mg every 12 h). However, a loading dose regimen with five administrations of either 400 or 600 mg was not sufficient to achieve the target Cmin (≥15 mg/L) for both routes. Also, PTAs for higher MIC (≥1.0 mg/L) were poor with all regimens for both routes.

Conclusions: This is the first study examining the pharmacokinetic/pharmacodynamic implications of using the sc route for teicoplanin. Subcutaneous administration is associated with lower Cmin and AUC values after the loading phase compared with iv administration. Therefore, iv administration should be preferred in the first few days of therapy. This study also shows that loading doses of teicoplanin higher than currently recommended should be used to improve PTA.
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http://dx.doi.org/10.1093/jac/dkx242DOI Listing
October 2017

Drowsiness and uncommon fever in a child after cannabis ingestion.

Ann Biol Clin (Paris) 2017 Aug;75(4):462-465

Laboratoire de pharmacologie et toxicologie, Hôpital Maison Blanche, CHU de Reims, Reims, France, SFR Cap-Santé-EA3801-Université de Reims, Laboratoire de pharmacologie médicale, Faculté de médecine de Reims, Reims, France.

Trivialization of cannabis consumption goes hand in hand with a growing exposure of children and the number of cannabis poisoning cases is steadily increasing. As clinical presentation can be different from what is currently seen in adults, added to the fact that it is not always suspected, diagnosis of cannabis intoxication in children is often delayed or missed. A 16-month-old girl was admitted to the pediatric emergency unit for an important drowsiness combined to moderate fever. After elimination of infectious causes, a toxic origin was considered and biological analyses led to the diagnosis of involuntary acute cannabis intoxication. In conclusion, cannabis intoxication in child has uncommon presentations compared to that seen in adults. In this context, biological analyses have a great importance for a rapid diagnosis and also for the understanding intoxication circumstance. This is of paramount importance because it may lead to consider child protection measures.
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http://dx.doi.org/10.1684/abc.2017.1261DOI Listing
August 2017

Therapeutic drug monitoring of mitotane: Analytical assay and patient follow-up.

Biomed Chromatogr 2017 Nov 21;31(11). Epub 2017 May 21.

Department of Pharmacology, Centre Hospitalier Universitaire de Reims, Reims, France.

Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal gland. Mitotane (o,p'-DDD) is the most effective chemotherapy for ACC. According to the literature, mitotane plasma trough concentrations within 14-20 mg L are correlated with a higher response rate with acceptable toxicity. Therapeutic drug monitoring (TDM) of mitotane is therefore recommended. The aim of this study was to propose a robust and simple method for mitotane quantification in plasma. The validation procedures were based on international guidelines. Sample preparation consisted of a single protein precipitation with methanol using 100 μL of plasma. The supernatant was submitted to liquid chromatography coupled with ultra-violet detection at 230 nm. Mitotane retention time was 7.1 min. The limit of detection was 0.1 mg L and the limit of quantification was 0.78 mg L . The assay demonstrated a linear range of 0.78-25 mg L with correlation coefficients (r ) at 0.999. Inter- and intra-assay precision was <4.85%. Evaluation of accuracy showed a deviation <13.69% from target concentration at each quality control level. This method proved easy and rapid to perform mitotane TDM and required a small volume of sample. It was successfully applied to routine TDM in our laboratory.
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http://dx.doi.org/10.1002/bmc.3993DOI Listing
November 2017

A Slight Smell of Lemon.

Ther Drug Monit 2017 06;39(3):205-207

*Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims Medecine University, Reims, France; and †Department of Pharmacology and Toxicology, Pharmacology and Toxicology Laboratory, Reims University Hospital, Reims Cedex, France.

We present here an example of urine substituted with a yellow cleaning product that leads us to develop the main risks to consider in urine toxicology analysis, ie, adulteration and analytical interferences, and how to deal with them. This grand round highlights the importance of the dialog between the clinician and a TDM consultant for optimal care of the patient.
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http://dx.doi.org/10.1097/FTD.0000000000000397DOI Listing
June 2017

Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years.

Antimicrob Agents Chemother 2016 08 22;60(8):4563-7. Epub 2016 Jul 22.

Hospices Civils de Lyon, Groupement Hospitalier de Gériatrie, Hôpital Antoine Charial, Service Pharmaceutique, Francheville, France UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université Lyon 1, Lyon, France ISPB, Faculté de Pharmacie, Université Lyon 1, Lyon, France.

Since the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (± standard deviations) of vancomycin volume of distribution and clearance were 36.3 ± 15.2 liter and 2.0 ± 0.9 liter/h, respectively. In the validation group, the bias and precision were -0.75 mg/liter and 8.76 mg/liter for population predictions and -0.39 mg/liter and 2.68 mg/liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin.
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http://dx.doi.org/10.1128/AAC.00303-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958150PMC
August 2016

Are ciprofloxacin dosage regimens adequate for antimicrobial efficacy and prevention of resistance? Pseudomonas aeruginosa bloodstream infection in elderly patients as a simulation case study.

Fundam Clin Pharmacol 2015 Dec 26;29(6):615-24. Epub 2015 Oct 26.

University Hospitals of Lyon, Pierre Garraud Hospital, Pharmacy. 136 rue du Commandant Charcot, Lyon, FR 69005, France.

The aim of this work was to define the optimal dosage (OD) of ciprofloxacin in order to prevent the emergence of bacterial resistance of Pseudomonas aeruginosa in a geriatric population with a bloodstream infection. A thousand pharmacokinetic profiles were simulated with a ciprofloxacin pharmacokinetic model from the literature. Three dosing regimens were tested for five days: once daily (QD), twice daily (BID), and thrice daily (TID). First of all, effective dosages (ED) of ciprofloxacin were defined as those achieving a target AUC24 /MIC ≥ 125. Then, these ED were simulated in order to calculate the percentage of time spent within the mutant selection window (TMSW ) and to select optimal dosage (OD) defined as those achieving TMSW ≤ 20%. Based on the AUC24 /MIC, for low MICs (0.125 μg/mL), all dosing regimens recommended by French guidelines were effective. For intermediate MICs (0.25 and 0.5 μg/mL), simulated doses higher than those recommended were needed to achieve the efficacy target. About prevention of resistance for low MICs, dosages recommended were only effective in patients with creatinine clearance (CLCR ) ≥ 60 mL/min. For intermediate MICs, dosages higher than recommended were needed to achieve the optimality target. This study shows that current ciprofloxacin dosing guidelines have not been optimized to prevent the emergence of bacterial resistance, especially in geriatric patients with mild to severe renal impairment. To achieve both efficacy and prevention of resistance, ciprofloxacin dosages greater than those recommended would be needed. Tolerance of such higher doses needs to be evaluated in clinical studies.
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http://dx.doi.org/10.1111/fcp.12156DOI Listing
December 2015

Polymorphisms in SLCO1B3 and NR1I2 as genetic determinants of hematotoxicity of carboplatin and paclitaxel combination.

Pharmacogenomics 2015 12;16(13):1439-50. Epub 2015 Aug 12.

Laboratoire de biochimie, Centre Hospitalier Universitaire (CHU) of Nîmes, Hôpital Carémeau, Nîmes, France.

Aim: The goal of our study was to assess the impact of patients' genetic background on their sensitivity to carboplatin/paclitaxel hematotoxicity.

Patients & Methods: Parameters describing sensitivity to neutropenia and to thrombocytopenia of 201 patients were extracted from a previous pharmacokinetic/pharmacodynamics analysis, in order to assess their association with 52 candidates SNPs in 18 genes.

Results: Carriers of a T allele of SLCO1B3-rs4149117 were 19% less sensitive to thrombocytopenia than the homozygotes for the G allele (p = 0.00279). Carriers of two copies of the ATG haplotypes of NR1I2-rs1523130, rs3814055 and rs1523127 were 19% less sensitive to thrombocytopenia than those harboring other haplotypes (p = 0.025).

Conclusion: Our results revealed the importance of SLCO1B3 and NR1I2 in the sensitivity to carboplatin/paclitaxel thrombocytopenia.
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http://dx.doi.org/10.2217/pgs.15.84DOI Listing
June 2016