title: The true distribution volume and bioavailability of mizoribine in children with chronic kidney disease.
abstract: BACKGROUND
  Mizoribine (MZR) is used kidney transplant and various kidney diseases. However, few studies reported the association between pharmacokinetics and pharmacodynamics. The Pharmacokinetics Study Group for Pediatric Kidney Disease (PSPKD) used population pharmacokinetics (PPK) analysis and Bayesian analysis to investigate the usefulness of MZR. In this study, the fact that almost all MZR are excreted unchanged in urine was used to calculate its bioavailability (F) and true distribution volume (Vd), and analyzed these correlation with age.
  
  
  METHODS
  Ishida et al. reported a PPK analysis by the PSPKD. In the present study, 71 samples extracted from their study population of 105 pediatric chronic kidney disease patients aged between 1 and 20 years were investigated. The bioavailability was calculated by measuring total excreted MZR in 24 h urine samples, and this was compared to the oral dosage. The apparent distribution volume (Vd/F) obtained from Bayesian analysis was then used to calculate true distribution volume (Vd), and the correlation of each parameter with age was investigated.
  
  
  RESULTS
  The median dose of MZR per weight was 5.17 mg/kg/day. Median bioavailability was 32.02%. Median Vdper weight was 0.46 L/kg. There was a significant, weakly positive correlation between bioavailability and age (p = 0.026). There was also a significant, weakly negative correlation between Vdper weight and age (p = 0.003).
  
  
  CONCLUSIONS
  Bioavailability and Vdper weight tended to decrease depending on age. The younger patient required larger dose required to obtain the maximum effect from MZR, and this is important for immunosuppressive therapy.
authors.affiliation: Division of Pediatric Nephrology, Department of Kidney Center, Aichi Medical University, 1-1, Nagakute City, Aichi, 480-1195, Japan. nagataku@aichi-med-u.ac.jp.
authors.forename: Takuhito
authors.identifier: http://orcid.org/0000-0002-7916-2963
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Pediatric Nephrology, Aichi Children's Health and Medical Center, Obu, Aichi, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Uemura
authors.affiliation: Department of Pediatrics, Toyama City Hospital, Toyama, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kaneda
authors.affiliation: Department of Pediatrics, Yokkaichi City Hospital, Mie, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ushijima
authors.affiliation: Department of Pediatrics, Kanazawa Medical Center, Kanazawa, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Kidney Center Pediatrics, Nagoya Daini Red Cross Hospital, Nagoya, Aichi, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Gotoh
authors.affiliation: Department of Pediatric Nephrology and Metabolism, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Satomura
authors.affiliation: Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Pediatrics, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Fujieda
authors.affiliation: Department of Pediatrics, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Morooka
authors.affiliation: Department of Pediatrics, Nagoya City West Medical Center, Aichi, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Pediatric Nephrology, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Pediatric Nephrology, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Wada
authors.affiliation: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001499:Bayes Theorem; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D054796:Drug Dosage Calculations; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D007223:Infant; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D008954:Models, Biological; D012076:Renal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D065667:Renal Elimination; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D012263:Ribonucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D012076:Renal Agents; D012263:Ribonucleosides; C010052:mizoribine
keywords: Bioavailability; Child; Distribution volume; Mizoribine; Pharmacokinetics