Search

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.

Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmaxwas increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax= 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach.