Pharmacokinetic analysis of ¹⁴C-ursodiol in newborn infants using accelerator mass spectrometry

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of ¹⁴C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of ¹⁴C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of ¹⁴C-ursodiol: 8ng (1.0nCi), 26ng (3.3nCi), and 80ng (10nCi) 48hours apart. Three additional infants with cholestasis were administered a single 80ng (10.0nCi) oral dose of ¹⁴C-ursodiol together with a therapeutic dose of 40mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research.