scholarly journals O28 Variability in liver anatomy and physiology in children participating in pharmacokinetic studies

2019 ◽  
Vol 104 (6) ◽  
pp. e12.2-e13
Author(s):  
A Friesen ◽  
J Radford ◽  
S Chan ◽  
N Mardis ◽  
V Shakhnovich
Keyword(s):  
Liver Volume ◽  
Pharmacokinetic Studies ◽  
List Type ◽  
Obese Children ◽  
Liver Anatomy ◽  
Anatomy And Physiology ◽  
Pbpk Models ◽  
Hepatic Volume ◽  
Hepatic Fat ◽  
Fat Fraction

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

Clinical Pharmacokinetic Studies in Pregnant Women and the Relevance of Pharmacometric Tools

2019 ◽  
Vol 25 (5) ◽  
pp. 483-495 ◽  
Author(s):  
André Dallmann ◽  
Paola Mian ◽  
Johannes Van den Anker ◽  
Karel Allegaert
Keyword(s):  
Pregnant Women ◽  
Clinical Pharmacokinetic ◽  
Individual Variability ◽  
Current Status ◽  
Pharmacokinetic Studies ◽  
Full Potential ◽  
Pbpk Models ◽  
Pregnancy And Postpartum ◽  
Population Pk ◽  
The Impact

Background: In clinical pharmacokinetic (PK) studies, pregnant women are significantly underrepresented because of ethical and legal reasons which lead to a paucity of information on potential PK changes in this population. As a consequence, pharmacometric tools became instrumental to explore and quantify the impact of PK changes during pregnancy. Methods: We explore and discuss the typical characteristics of population PK and physiologically based pharmacokinetic (PBPK) models with a specific focus on pregnancy and postpartum. Results: Population PK models enable the analysis of dense, sparse or unbalanced data to explore covariates in order to (partly) explain inter-individual variability (including pregnancy) and to individualize dosing. For population PK models, we subsequently used an illustrative approach with ketorolac data to highlight the relevance of enantiomer specific modeling for racemic drugs during pregnancy, while data on antibiotic prophylaxis (cefazolin) during surgery illustrate the specific characteristics of the fetal compartments in the presence of timeconcentration profiles. For PBPK models, an overview on the current status of reports and papers during pregnancy is followed by a PBPK cefuroxime model to illustrate the added benefit of PBPK in evaluating dosing regimens in pregnant women. Conclusions: Pharmacometric tools became very instrumental to improve perinatal pharmacology. However, to reach their full potential, multidisciplinary collaboration and structured efforts are needed to generate more information from already available datasets, to share data and models, and to stimulate cross talk between clinicians and pharmacometricians to generate specific observations (pathophysiology during pregnancy, breastfeeding) needed to further develop the field.

scholarly journals Alanine Aminotransferase Levels and Fatty Liver in Childhood Obesity: Associations with Insulin Resistance, Adiponectin, and Visceral Fat

2006 ◽  
Vol 91 (11) ◽  
pp. 4287-4294 ◽  
Author(s):  
Tania S. Burgert ◽  
Sara E. Taksali ◽  
James Dziura ◽  
T. Robin Goodman ◽  
Catherine W. Yeckel ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Fatty Liver ◽  
Visceral Fat ◽  
Resonance Imaging ◽  
Fat Accumulation ◽  
Glucose And Lipid Metabolism ◽  
The Metabolic Syndrome ◽  
Hepatic Fat ◽  
Fat Fraction

Abstract Background: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. Methods: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. Findings: Elevated ALT (&gt;35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18–35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. Interpretation: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.

scholarly journals Dietary determinants of hepatic fat content and insulin resistance in overweight/obese children: a cross-sectional analysis of the Prevention of Diabetes in Kids (PREDIKID) study

2019 ◽  
Vol 121 (10) ◽  
pp. 1158-1165 ◽  
Author(s):  
Lide Arenaza ◽  
María Medrano ◽  
Maddi Oses ◽  
Inge Huybrechts ◽  
Ignacio Díez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Dietary Intake ◽  
Dietary Habits ◽  
Sugar Content ◽  
Model Assessment ◽  
Obese Children ◽  
Cross Sectional ◽  
Alcoholic Fatty Liver ◽  
Sugar Intake ◽  
Hepatic Fat

AbstractPaediatric non-alcoholic fatty liver disease has increased in parallel with childhood obesity. Dietary habits, particularly products rich in sugars, may influence both hepatic fat and insulin resistance (homeostatic model assessment for insulin resistance (HOMA-IR)). The aim of the study was to examine the association of the consumption of foods and food components, dairy desserts and substitutes (DDS), sugar-sweetened beverages (SSB), as well as total and added sugars, with hepatic fat and HOMA-IR. Dietary intake (two non-consecutive 24 h-recalls), hepatic fat (MRI) and HOMA-IR were assessed in 110 overweight/obese children (10·6 (sd 1·1) years old). Linear regression analyses were used to examine the association of dietary intake with hepatic fat and HOMA-IR adjusted for potential confounders (sex, age, energy intake, maternal educational level, total and abdominal adiposity and sugar intake). The results showed that there was a negative association between cereal intake and hepatic fat (β=–0·197, P<0·05). In contrast, both SSB consumption (β=0·217; P=0·028) and sugar in SSB (β=0·210, P=0·035), but not DDS or sugar in DDS or other dietary components, were positively associated with hepatic fat regardless of potential confounders including total sugar intake. In conclusion, cereal intake might decrease hepatic fat, whereas SSB consumption and its sugar content may increase the likelihood of having hepatic steatosis. Although these observations need to be confirmed using experimental evidence, these results suggest that healthy lifestyle intervention programs are needed to improve dietary habits as well as to increase the awareness of the detrimental effects of SSB consumption early in life.

PS-112-Endoscopic duodenal mucosal resurfacing improves hepatic fat fraction, glycemic and lipid profiles in type 2 diabetes

2019 ◽  
Vol 70 (1) ◽  
pp. e70-e71 ◽  
Author(s):  
Guruprasad Aithal ◽  
Naomi Sakai ◽  
Manil Chouhan ◽  
David Hopkins ◽  
Rachel Batterham ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lipid Profiles ◽  
Hepatic Fat ◽  
Fat Fraction

Evaluation of the changes in hepatic apparent diffusion coefficient and hepatic fat fraction in healthy cats during body weight gain

2020 ◽  
Vol 81 (10) ◽  
pp. 796-803 ◽  
Author(s):  
Gian-Luca Steger ◽  
Elena Salesov ◽  
Henning Richter ◽  
Claudia E. Reusch ◽  
Patrick R. Kircher ◽  
...  
Keyword(s):  
Body Weight ◽  
Diffusion Coefficient ◽  
Weight Gain ◽  
Apparent Diffusion Coefficient ◽  
Body Weight Gain ◽  
Apparent Diffusion ◽  
Hepatic Fat ◽  
Fat Fraction

scholarly journals Comparison of 1H MR Spectroscopy, 3-point DIXON, and Multi-echo Gradient Echo for Measuring Hepatic Fat Fraction

2011 ◽  
Vol 10 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Kinya ISHIZAKA ◽  
Noriko OYAMA ◽  
Suzuko MITO ◽  
Hiroyuki SUGIMORI ◽  
Mitsuhiro NAKANISHI ◽  
...  
Keyword(s):  
Mr Spectroscopy ◽  
Gradient Echo ◽  
1H Mr Spectroscopy ◽  
Hepatic Fat ◽  
Fat Fraction

Hepatic Fat Fraction: MR Imaging for Quantitative Measurement and Display—Early Experience

Radiology ◽  
2005 ◽  
Vol 237 (3) ◽  
pp. 1048-1055 ◽  
Author(s):  
Hero K. Hussain ◽  
Thomas L. Chenevert ◽  
Frank J. Londy ◽  
Vikas Gulani ◽  
Scott D. Swanson ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Quantitative Measurement ◽  
Early Experience ◽  
Hepatic Fat ◽  
Fat Fraction

scholarly journals Effect of hepatocyte-specific gadolinium-based contrast agents on hepatic fat-fraction and R2⁎

2015 ◽  
Vol 33 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Diego Hernando ◽  
Shane A. Wells ◽  
Karl K. Vigen ◽  
Scott B. Reeder
Keyword(s):  
Contrast Agents ◽  
Hepatic Fat ◽  
Fat Fraction

Active and passive control of hepatic blood volume responses to hemorrhage at normal and raised hepatic venous pressure in cats

1980 ◽  
Vol 58 (9) ◽  
pp. 1049-1057 ◽  
Author(s):  
W. Wayne Lautt ◽  
L. Cheryle Brown ◽  
J. Scott Durham
Keyword(s):  
Blood Flow ◽  
Blood Loss ◽  
Blood Volume ◽  
Passive Control ◽  
Venous Pressure ◽  
Liver Volume ◽  
Passive Flow ◽  
Hepatic Volume ◽  
Volume Response

Hepatic blood volume decreases in response to a rapid hemorrhage (15.3 mL/min) were measured in cats anesthetized with pentobarbital or ketamine–chloralose, by use of in vivo plethysmography alone or in combination with various surgical procedures and vascular circuits. The hepatic blood volume contracts during hemorrhage to compensate for a constant proportion (26 ± 6%) of the blood loss regardless of the extent of the actual blood loss. Following denervation of the liver and α adrenoreceptor blockade (3 mg phentolamine, intraportal) the liver compensation was unaltered. After denervation, nephrectomy, hypophysectomy, and adrenalectomy the liver was still able to compensate for 20 ± 7.4% of the hemorrhage. Decreases in liver volume were linearly related to decreases in total hepatic blood flow that ensued whether the decreased blood flow was induced by hemorrhage or by clamping of the arteries supplying the splanchnic organs (superior mesenteric artery, celiac artery). The hepatic volume response to hemorrhage could be predicted accurately (97 ± 6.6%) simply from the linear passive relationship between flow and volume for a particular animal. However when hepatic venous pressure was experimentally elevated, the volume response to passive flow decrease was markedly reduced whereas the response to hemorrhage and noradrenaline infusion was unimpaired suggesting that active control factors were required to produce normal hepatic volume responses to hemorrhage at raised venous pressure. Phentolamine reduced the response at raised venous pressure but was without effect at normal venous pressure in the same animal, indicating that the hepatic nerves and (or) adrenal catecholamines are of paramount importance in control of the response at raised venous pressure when the passive flow influence is much reduced.

Sign in / Sign up

Export Citation Format

Share Document