title: Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children.
abstract: BACKGROUND
  6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.
  
  
  METHODS
  The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.
  
  
  RESULTS
  The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.
  
  
  CONCLUSIONS
  Pharmacokinetic, palatability and safety data support the use of Loulla in children.
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics and Clinical Investigations Center CIC1426 INSERM, Robert Debre Hospital, Assistance Publique Hopitaux de Paris, Paris, France. Electronic address: tiphaine.debeaumais@rdb.aphp.fr.
authors.forename: Adam de Beaumais
authors.initials: Ade B
authors.lastname: Tiphaine
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital, Copenhagen, Denmark.
authors.forename: Lisa Lynqsie
authors.initials: LL
authors.lastname: Hjalgrim
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nersting
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Universitätsstrasse 1, Düsseldorf, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Breitkreutz
authors.affiliation: Department of Paediatric Haematology/Oncology, University Hospital of Jeanne de Flandre, Lille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nelken
authors.affiliation: University Medical Center Schleswig-Holstein, Campus Kiel Schwanenweg, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Medical Scholl Hannover, Department of Pediatric Hematology and Oncology, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Immunohematology and Pediatric Oncology Department, Mother Child Hospital, Nantes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Institute of Haematology and Paediatric Oncology, Hospices Civils de Lyon, Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: UPMC University Paris 06, Paediatric Haematology Oncology Unit, Armand Trousseau Hospital, Assistance Publique Hopitaux de Paris, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Leverger
authors.affiliation: Paediatric Immunology and Haematology Department, Robert Debre Hospital, Assistance Publique Hopitaux de Paris, Paris, France; University Paris VII Diderot, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics and Clinical Investigations Center CIC1426 INSERM, Robert Debre Hospital, Assistance Publique Hopitaux de Paris, Paris, France; University Paris VII Diderot, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002648:Child; D006224:Cricetinae; D018592:Cross-Over Studies; D004304:Dosage Forms; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D015122:Mercaptopurine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000378:metabolism*; D055697:Taste Perception; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D004304:Dosage Forms; D015122:Mercaptopurine
keywords: 6-mercaptopurine; Bioavailability; Leukemia; Liquid formulation; Pediatrics; Pharmacokinetics