title: Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.
abstract: BACKGROUND
  A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation.
  
  
  METHODS
  Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m2) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed.
  
  
  RESULTS
  No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUCN(where AUC is area under the curve), CmaxN, and Tmax. Comparisons within each group revealed significant differences in AUC0-∞and Tmaxin the 5 mg/ml group.
  
  
  CONCLUSIONS
  Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.
authors.affiliation: Divisions of Hematology/Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.|Divisions of Clinical Pharmacology, Medical Toxicology, and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.|Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Jaszianne A
authors.initials: JA
authors.lastname: Tolbert
authors.affiliation: Arkansas Children's Hospital Research Institute, Arkansas Children's Hospital, Little Rock, Arkansas.|Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Shasha
authors.initials: S
authors.lastname: Bai
authors.affiliation: Divisions of Clinical Pharmacology, Medical Toxicology, and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.|Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Abdel-Rahman
authors.affiliation: Divisions of Hematology/Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.|Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: August
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Missouri-Kansas City, Kansas City, Missouri.|Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas.|University of Kansas Cancer CenterKansas City, Kansas.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weir
authors.affiliation: Divisions of Clinical Pharmacology, Medical Toxicology, and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.|Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kearns
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.|Sections of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital, Little Rock, Arkansas.|Sections of Pediatric Hematology Oncology, Arkansas Children's Hospital, Little Rock, Arkansas.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Neville
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004304:Dosage Forms; D005260:Female; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry
chemical_list: D000964:Antimetabolites, Antineoplastic; D004304:Dosage Forms; D015122:Mercaptopurine
keywords: ALL; pediatric oncology; pharmacokinetics