Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period

Clin Pharmacol Ther. 2009 Jan;85(1):56-63. doi: 10.1038/clpt.2008.177. Epub 2008 Sep 17.


The phosphodiesterase 5 inhibitor sildenafil is a potential therapeutic option in the treatment of persistent pulmonary hypertension of the newborn (PPHN) and neonatal hypoxemia. In this open-label trial, 36 term neonates with PPHN or hypoxemia were administered intravenous sildenafil for up to 7 days starting within 72 h of birth. A mixed-effects pharmacokinetic model that included two-compartment disposition of sildenafil and its metabolite and an effect of postnatal age on sildenafil clearance was used to describe plasma concentration-time data of parent and metabolite. Allometrically scaled sildenafil clearance increased threefold from the first day after birth to values similar to those in adults by the first week. Volume of distribution of sildenafil in neonates was fourfold higher than in adults, resulting in a longer terminal half-life in neonates (48-56 h) compared to adults. Increase in sildenafil clearance in the early postnatal period likely reflects maturation of CYP-mediated N-demethylation.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Availability
  • Female
  • Half-Life
  • Humans
  • Infant, Newborn
  • Infusions, Intravenous
  • Male
  • Metabolic Clearance Rate
  • Persistent Fetal Circulation Syndrome / drug therapy*
  • Phosphodiesterase Inhibitors / blood
  • Phosphodiesterase Inhibitors / pharmacokinetics*
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Piperazines / blood
  • Piperazines / pharmacokinetics*
  • Piperazines / therapeutic use*
  • Purines / blood
  • Purines / pharmacokinetics
  • Purines / therapeutic use
  • Pyrimidinones / pharmacokinetics*
  • Sildenafil Citrate
  • Sulfones / blood
  • Sulfones / pharmacokinetics*
  • Sulfones / therapeutic use*


  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Pyrimidinones
  • Sulfones
  • UK 103320
  • Sildenafil Citrate