Publications by authors named "Jean Szymezak"

10 Publications

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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

Multicentre pharmacokinetic evaluation of rFVIII-Fc (efmoroctocog alfa) in a real life and comparison with non-extended half-life FVIII concentrates.

Haemophilia 2020 Mar 27;26(2):282-289. Epub 2020 Feb 27.

Laboratoire d'Hémostase Hémobiologie, CHU de Lille, Lille, France.

The use of enhanced half-life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII-Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non-EHL FVIII. The in vivo recovery (IVR) of rFVIII-Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half-life (T ) of rFVIII-Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII-Fc vs non-EHL FVIII showed a T ratio of 1.4 in favour of rFVIII-Fc, regardless of the patient's age. However the relative increase in T with rFVIII-Fc was lower than 30% in one-third of patients evaluated, particularly when the previous FVIII administered was a BHK-derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.
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http://dx.doi.org/10.1111/hae.13946DOI Listing
March 2020

Evolution of platelet functions in cirrhotic patients undergoing liver transplantation: A prospective exploration over a month.

PLoS One 2018 2;13(8):e0200364. Epub 2018 Aug 2.

AP-HP, European University Hospital Georges Pompidou, Hematology Department, Paris, France.

This prospective observational study was designed to analyze platelet functions across time in 50 patients scheduled for liver transplantation (LT) secondary to decompensated cirrhosis or hepatocellular carcinoma. Platelet functions were assessed before LT (pre-LT), one week (D7) and 1 month (D28) after LT. Platelet count significantly increased from pre-LT time to day 28 as well as circulating CD34+hematopoietic stem cells. To avoid any influence of platelet count on assays, platelet function was evaluated on platelet-rich-plasma adjusted to pre-LT platelet count. Although platelet secretion potential did not differ between time-points, as evaluated by the expression of CD62P upon strong activation, platelet aggregation in response to various agonists significantly increased along time, however with no concomitant increase of circulating markers of platelet activation: platelet microvesicles, platelet-leukocyte complexes, soluble CD40L and soluble CD62P. In the multivariate analysis, hepatic function was associated with platelet count and function. A lower platelet aggregation recovery was correlated with Child C score. History of thrombosis or bleeding was associated with respective higher or lower values of platelet aggregation. This longitudinal analysis of platelet functions in LT patients showed an improvement of platelet functions along time together with platelet count increase, with no evidence of platelet hyperactivation at any time-point.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072007PMC
January 2019

Tissue factor expressed by adherent cells contributes to hemodialysis-membrane thrombogenicity.

Thromb Res 2016 Aug 27;144:218-23. Epub 2016 May 27.

Equipe d'accueil 3801 Hémostase et Remodelage Vasculaire Post-Ischémie, Université de Reims, France. Electronic address:

End-stage renal patients present a high risk of thrombosis and bleeding. Consequently, it is challenging to prevent clotting during hemodialysis. If a contact system induces thrombin generation in the extra corporeal circuit, recent data suggest a role of tissue factor (TF) in hemodialysis-associated thrombosis. Using a method of elution, we collected adhering cells to an acrylonitrile membrane layered by polythyleneimine (AN69-ST). Using optic microscopy and flow cytometry, we observed that adherent cells were mainly constituted by activated polymorphonuclear neutrophils (PMNs). Using a sensitive fluorogenic method of thrombin generation, we found that adhering cells triggered thrombin generation in a TF-dependent manner. We next identified the presence of TF mRNA (Q-PCR) in adhering cells. Using immunofluorescence, we observed the presence of TF in PMNs and of TF-decorated neutrophil extracellular traps (NETs). As TF triggers thrombin generation after binding to serine protease FVIIa, we evaluated the effect of an inactivated human recombinant factor VIIa (hrFVIIai) in a sheep model of hemodialysis (HD). One single bolus of hrFVIIai maintained the full patency of the hemodialysis circuit without any measurable systemic anticoagulant effect. TF is a promising target for preventing thrombosis during HD.
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http://dx.doi.org/10.1016/j.thromres.2016.05.017DOI Listing
August 2016

Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers.

Arch Cardiovasc Dis 2013 Dec 15;106(12):661-71. Epub 2013 Nov 15.

Inserm, CIC-9304 and UMRS-956, Paris, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-9304, Paris, France; UPMC Univ Paris 06, Faculty of Medicine, Department of Pharmacology and UMRS-956, Paris, France. Electronic address:

Background: Several studies have suggested that proton-pump inhibitors (PPIs), mostly omeprazole, interact with clopidogrel efficacy by inhibiting the formation of its active metabolite via CYP2C19 inhibition. Whether this occurs with all PPIs is a matter of debate. As rabeprazole is a less potent CYP2C19 inhibitor than other PPIs, we studied the interaction between rabeprazole and the antiplatelet actions and pharmacokinetics of clopidogrel.

Aim: To demonstrate the non-inferiority of rabeprazole over placebo using change in platelet reactivity index (PRI; vasodilator-stimulated phosphoprotein [VASP] assay) in a predefined population of good clopidogrel responders. Omeprazole was used as the positive control.

Methods: In this randomized three-period crossover study in healthy volunteers, 36 healthy men received clopidogrel (75 mg/day for 7 days) with placebo, omeprazole (20mg/day) or rabeprazole (20mg/day). Clopidogrel antiplatelet effects and disposition kinetics were assessed on day 7 of combination therapy. Non-inferiority threshold was predefined as an upper limit of the 90% confidence interval for the difference in change in PRI between placebo and rabeprazole of<10% in good clopidogrel responders.

Results: In good clopidogrel responders (inhibition of VASP index>30%), the clopidogrel antiplatelet effect remained non-inferior to placebo during rabeprazole (difference 3.4% [-1.7; 8.5]) but not omeprazole (difference 7.5% [2.5; 12.6]) co-administration. The AUC0-24 and Cmax of active clopidogrel metabolite decreased with both omeprazole and rabeprazole, and conditions of bioequivalence were not met, except for AUC0-24 with rabeprazole.

Conclusions: Rabeprazole does not interact with clopidogrel to the same extent as omeprazole. However, under our experimental conditions and proton-pump inhibitor doses, there was no significant pharmacodynamic interaction between rabeprazole or omeprazole and clopidogrel, despite a significant decrease in the formation of clopidogrel active metabolite.
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http://dx.doi.org/10.1016/j.acvd.2013.09.002DOI Listing
December 2013

Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation.

J Cardiol 2012 Jan 17;59(1):30-5. Epub 2011 Nov 17.

Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Angiogenic cytokines have been shown to influence vessel injury, and platelets represent a disposable circulating pool of angiogenic molecules. In the present study, objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation. We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/day. We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor (VEGF)-A and its soluble receptor forms VEGFR1 and VEGFR2, placenta growth factor, and stromal cell-derived factor-1. We also quantified soluble E-selectin and von Willebrand factor to evaluate endothelial activation. Blood samples were drawn just before the first clopidogrel intake on day 1, and after the last dosing (day 7). As expected, we observed a decrease in platelet reactivity in response to clopidogrel, confirmed by vasodilator-stimulated phosphoprotein phosphorylation assay. However, the 7-day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation. These results show that circulating angiogenic factor level in healthy subjects is not driven by P2Y12 platelet receptor-induced activation and clopidogrel does not modify in a significant way the endothelial activation level.
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http://dx.doi.org/10.1016/j.jjcc.2011.09.002DOI Listing
January 2012

Evaluation of the DCA Vantage analyzer for HbA 1c assay.

Clin Chem Lab Med 2008 ;46(8):1195-8

Laboratory of Pediatric Biology and Research, American Memorial Hospital, University Hospital of Reims, Reims, France.

Background: Measurement of HbA 1c is key in monitoring diabetic patients in both laboratories and clinical units, where HbA 1c results are used as part of patient education.

Methods: We have evaluated the DCA Vantage, a new device for immunological assay of HbA 1c. HbA 1c results obtained were evaluated in terms of precision, linearity, specificity and practicability, and were compared with results obtained by a Variant II HPLC method.

Results: The method exhibited intra- and inter-assay coefficients of variation lower than 2.6% and 4.0%, respectively, and good correlation with the comparison HPLC method (r2=0.9776). No interference was noted in the presence of labile HbA 1c or carbamylated hemoglobin. The new device exhibited improved practicability characteristics and allowed better sample identification, better management of quality control routines and greater connectivity possibilities compared to the previous DCA 2000 analyzer.

Conclusions: This new analyzer exhibited analytical and practical characteristics very suitable for HbA 1c assay for laboratory or point-of-care use according to good laboratory practice.
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http://dx.doi.org/10.1515/CCLM.2008.228DOI Listing
October 2008