BackgroundObesity-related changes in liver anatomy and physiology (e.g., hepatic fat infiltration) may be important sources of interindivdual variability in hepatic drug metabolism and relevant covariates for physiologically-based pharmacokinetic (PBPK) models. The aim of this investigation was to quantify variability in hepatic fat fraction (HFF) and hepatic volume in children participating in PK studies, utilizing a novel, non-invasive, magnetic resonance imaging (MRI) sequence.1MethodsChildren, without a known diagnosis of fatty liver disease, enrolled in a PK study for hepatic CYP2C19 and CYP3A4 substrates, had hepatic volume and total HFF estimated using MRI proton density fat fraction (PDFF) and HFF assessed via conventional MRI spectroscopy (MRSFF) using a region of interest in the right upper hepatic lobe (LiverLab, Siemens Healthcare). Patient anthropometrics, laboratories and LiverLab outcomes were compared between obese and non-obese children, using independent student t-test, and associations explored via Spearman’s correlation (ρ); SPSSv24, α=0.05. Obesity was defined by body mass index (BMI)≥95th percentile for age; clinically significant liver adiposity defined as HFF>5%.Results25 children (7–20 years; 56% obese) had evaluable MRI data. Liver volume ranged 911–2227cm3, MRSFF 1.6–34.8% and PDFF 2.1–31.1%. Liver volume and HFF significantly correlated with BMI (both ρ=0.6, p< 0.01), but not age (both ρ=0.3, p>0.11). Liver volume (1574.5±367.1 vs 1284.8±216.3, p=0.04), MRSFF (8.9±8.4 vs 2.8±1.2, p=0.02), PDFF (8.9±7.0 vs 3.4±1.3, p=0.07) and alanine aminotransferase (ALT; 37.7±15.8 vs 26.8±3.6 IU/L, p=0.02) were higher in obese vs non-obese children. HFF>5% and ALT> 40 were only observed in obese children.ConclusionLiver volume and adiposity varied substantially among children and may be important covariates for pediatric PBPK models, especially for obese children. HFF> 5% and ALT> 40 were only observed in obese children. Recently, 24% reduction in clearance of azithromycin, a CYP3A4 substrate, was reported for children with ALT> 40.2 Our PK analyses are in progress.ReferencesCaussy C, Reeder SB, Sirlin CB, et al. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as as endpoint in NASH trials. Haptology 2018;68(2):763–72.Zheng Y, Liu SP, Xu BP, et al. Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia. Antimicrob Agents Chemother 2018;62 (9):e00686–18.Disclosure(s)Nothing to disclose