RT Journal Article
SR Electronic
T1 How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1090
OP 1098
DO 10.1124/dmd.115.068643
VO 44
IS 7
A1 Trevor N. Johnson
A1 Masoud Jamei
A1 Karen Rowland-Yeo
YR 2016
UL http://dmd.aspetjournals.org/content/44/7/1090.abstract
AB Information on the developmental changes in biliary excretion (BE) of drugs is sparse. The aims of this study were to collate literature data on the pharmacokinetics of biliary excretion of drugs used in pediatrics and to apply a physiologically based pharmacokinetic (PBPK) model to predict their systemic clearance (CL) with a view to elucidating age-related changes in biliary excretion. Drug parameters for azithromycin, ceftriaxone, and digoxin administered intravenously and buprenorphine (intravenous and sublingual) were collated from the literature and used in the Simcyp Simulator to predict adult CL values, which were then validated against observed data. The change in CL with age was simulated in the pediatric model and compared with observed data; where necessary, the ontogeny function associated with BE was applied to recover the age-related CL. For azithromycin a fraction of adult BE activity of 15% was necessary to predict the CL in neonates (26 weeks gestational age) and 100% activity was apparent by 7 months. For ceftriaxone and digoxin full BE activity appeared to be present at term birth; for digoxin, an adult BE activity of 10% was needed to predict the CL in premature neonates (30 weeks gestational age). The CL of buprenorphine with age was described by the ontogeny of the major elimination pathways (CYP3A4 and UGT1A1) with no ontogeny assumed for the biliary component. Thus, the ontogeny of BE for all four drugs appears to be rapid and they attain adult levels at birth or within the first few months of postnatal age.