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Pharmacokinetic Study of Metopimazine by Oral Route In Pharmacokinetic study of metopimazine by oral route in children Eric Mallet, Fréderic Bounoure, Mohamed Skiba, Elodie Saussereau, Jean-Pierre Goullé, Mireille Castanet To cite this version: Eric Mallet, Fréderic Bounoure, Mohamed Skiba, Elodie Saussereau, Jean-Pierre Goullé, et al.. Phar- macokinetic study of metopimazine by oral route in children. Pharmacology Research & Perspectives, Wiley, 2015, 3 (3), pp.e00130. 10.1002/prp2.130. hal-02470837 HAL Id: hal-02470837 https://hal-normandie-univ.archives-ouvertes.fr/hal-02470837 Submitted on 29 Jun 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives| 4.0 International License ORIGINAL ARTICLE Pharmacokinetic study of metopimazine by oral route in children Eric Mallet1, Frederic Bounoure2, Mohamed Skiba2, Elodie Saussereau3, Jean-Pierre Goulle3 & Mireille Castanet1 1CIC INSERM 204, Department of Pediatrics, Rouen University Hospital, Charles Nicolle, 76031 Rouen, France 2Pharmaceutics Laboratory (UMR CNRS 5007), Faculty of Medicine and Pharmacy, Rouen University, 76183 Rouen, France 3Laboratoire de pharmacocinetique et de toxicologie cliniques, Groupe Hospitalier du Havre, BP 24, 76083 Le Havre, France Keywords Abstract Antiemetic drug, children, metopimazine, pharmacokinetics. Metopimazine (MPZ) is an antiemetic considered as a currently used drug. In France, it has become the leading antiemetic mediator due to its good tolerance, Correspondence however, its pharmacokinetics has never previously been studied in children. Eric Mallet, Department of Pediatrics, 1, Rue MPZ was administered by oral route to 8 children with a single dose of 0.33 mg/ de Germont, Rouen University Hospital- kg during an endocrine exploration using stimuli well known for its adverse eme- Charles Nicolle, 76031 Rouen, France. tic effects. We used biological remnants from sera following an hGH test in order Tel: +33 6 82 39 6224; Fax: +33 2 32 88 to obtain the MPZ pharmacokinetics. Plasmatic concentrations of MPZ and the 8676; E-mail: [email protected] active acid metabolite AMPZ, were quantified by HPLC-MS/MS during a 270 min test period. MPZ is quickly absorbed with a median Cmax of 17.2 ng/ Funding Information mL at one hour and its half-life is 2.18 h. The plasmatic concentrations of AMPZ Research was carried out under the French were higher than MPZ with a median Cmax of 76.3 ng/mL, a Tmax to 150 min National Research Programs CIC INSERM 204 and its concentration was approximately maintained at 50 ng/mL from 1 to 4 h. and UMR CTNS 5007. The plasmatic concentrations in children are similar to those observed in adults. No adverse effects, nausea or vomiting occurred during the trial. Therefore, these Received: 11 August 2014; Revised: 26 January 2015; Accepted: 3 February 2015 results confirm the MPZ dosage that should be used in children under 15 kg administered as 0.33 mg/kg up to 3 times a day. Pharma Res Per, 3(3), 2015, e00130, doi: 10.1002/prp2.130 Abbreviations AMPZ, active metopimazine; API, atmospheric pressure ionization; AUC, area doi: 10.1002/prp2.130 under the curve; BMI, body mass index; CTD, common technical document; ESI, electrospray ionization interface; hGH, human growth hormone; LOD, limit of detection; LOQ, limit of quantification; MPZ, metopimazine; MRM, multiple reac- tion monitoring. Introduction The transdermal route has been also studied but the low percutaneous absorption of MPZ limits the development Metopimazine (MPZ) has been commercialized for the of a transdermal form (Bounoure et al. 2008). The drug past 30 years in France and is considered as a currently only acts on area postrema receptors and peripheral recep- used drug. This medication is frequently used to treat tors due to its low brain penetration. Jolliet et al. (2007) nausea or vomiting especially during acute gastroenteritis. showed that MPZ brain penetration is lower than dom- It is a phenothiazine derivate which is an antidopaminer- peridone and metoclopramide, as well as the main MPZ gic D2 receptor antagonist. In France, MPZ is sold under metabolite, the acid metabolite AMPZ which also exhibits various pharmaceutical forms. Hard capsules, supposito- a very low blood brain barrier permeability which ries, injectable solutions and orodispersible tablets are explains its good tolerance to MPZ. available for adults and a solution or suppositories for MPZ is also a medication with a satisfactory therapeu- children. Different drug administration routes can be cho- tic balance. Herrstedt et al. (1997) reported the MPZ tol- sen to adapt the treatment to the patient’s requirements. erance administered via the oral route at large doses in ª 2015 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, 2015 | Vol. 3 | Iss. 3 | e00130 British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Page 1 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Pharmacokinetic Study of Metopimazine E. Mallet et al. adults. These authors concluded that the tolerance residues remaining after serum human growth hormone remained acceptable at a dose of 180 mg/day 30 mg 9 6 (hGH) tests were performed for children explored in a and at a higher dose, primary side effect was dizziness day hospital for assessment of their small size. caused by orthostatic hypotension. The organic residues obtained from these children were The low brain penetration is thought to be the reason used to perform a stimulation test for hGH secretion why MPZ side effects are different from the other pheno- using two stimuli, betaxolol and glucagon secretory thiazine compounds. The rare neurologic side effects are response and assessed over a 4 h period by repeated sedation, drowsiness and extrapyramidal syndrome which blood sampling. As the test is known to cause nausea or are reversible once the drug is stopped. This possible vomiting, this justified the oral administration of MPZ extrapyramidal adverse event was reported by Herrstedt 30 min before starting the test. Biological collection et al. (1997) in a single patient with a very high dose of obtained from organic residues of this exploration of the 360 mg per day. The a1 adrenergic antagonist activity hGH secretion kinetics, permitted us to also assess the causes orthostatic hypotension and dizziness. MPZ is also kinetics of MPZ administered orally at the recommended a low muscarinic cholinergic antagonist which can gener- dose in children under 7 years of age. ate urine retention, visual disorder, constipation or dry mouth (Herrstedt et al. 1993). These rare side effects are Study design described in the CTD. Two recent notices from the French Drug Agency Eight children explored at a day hospital for an evaluation (ANSM) on domperidone and metoclopramide MPZ of their small size, were included in a biological collection defined by default as the reference antiemetic medication study. There were 4 boys and 4 girls, 2 to 6 years of age due to its good tolerance. Currently, metoclopramide is with a body mass index (BMI) in kg/m2 which ranged contraindicated for children because of the high propor- from 13.5 to 17.5 for boys and 13.7 to 17.9 for girls. After tion of major neurologic side effects such as extrapyrami- individual child selection all parents received written dal syndrome (ANSM 2012). Also, the daily dose of information regarding the study, and a signed informed domperidone has been decreased for the elderly people consent was obtained as recommended by the Committee because of a risk of cardiac arrhythmia or sudden death for the Protection of Individuals in the North West (ANSM 2011). Region of France. MPZ pharmacokinetics has been previously studied in A complete biological evaluation was conducted to assess adults and a number of series have been reported in the the children’s small size. The results confirmed a normal literature. For Herrstedt et al. (1996) the oral bioavail- liver and kidney function. The hGH secretion test protocol ability of MPZ was approximately 22.3%. This low value results were as follows: Time minus 30 min, oral adminis- â is due to a liver deamination into MPZ acid. The oral tration of MPZ (Vogalene ; Teva Laboratory, Courbevoie, route only increases the area under the curve (AUC) France) solution 0.1% at the recommended dosage for the ratio between MPZ acid and MPZ, that is, 13.7 by oral particular age, that is, standard pharmaceutical reference administration and 2.5 by intravenous administration. found in the standard French pharmaceutical reference For these authors the postprandial oral administration of manual common technical document (CTD), that is, â MPZ reduces the AUC of MPZ by 30% (Herrstedt et al. 0.33 mg/kg, and a beta blocker (Kerlone or betaxolol 1990). hydrochloride; Sanofi-Aventis, Paris, France) at a dose of Currently, to our knowledge, no study has been pub- 2.5 mg/kg (Herrstedt et al. 1990). Installation of the first lished regarding MPZ pharmacokinetics in children. The venous injection time 0 test administration by intravenous â â aim of this study was to validate the currently used pedi- injection of glucagon (i.e., Glucagen ; Novo Nordisk La atric dosage of 0.33 mg/kg 3 times a day in children De´fense - Paris, France) at a dose of 0.03 mg/kg.
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