title: Plasma concentrations of tadalafil in children with pulmonary arterial hypertension.
abstract: BACKGROUND
  There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug.
  
  
  METHODS
  Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration.
  
  
  RESULTS
  Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL).
  
  
  CONCLUSIONS
  We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.
authors.affiliation: *Department of Clinical Pharmacy, Graduate School of Medicine and Pharmaceutical Sciences; †Department of Pediatrics and ‡First Department of Surgery, Faculty of Medicine, University of Toyama; and §Department of Pediatrics, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kohno
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hirono
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ozawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Chisato
authors.initials: C
authors.lastname: Akita
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
mesh_terms: D000293:Adolescent; D000375:Aging; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077300:Bosentan; D002243:Carbolines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D007223:Infant; D008297:Male; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068581:Tadalafil; D014665:Vasodilator Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D002243:Carbolines; D013449:Sulfonamides; D014665:Vasodilator Agents; D000068581:Tadalafil; D000077300:Bosentan