scholarly journals Piecing together human adult comparative pharmacokinetic trials and rodent studies: What happens to drug clearance in obesity?

2022 ◽  
Vol 25 ◽  
pp. 41-68
Author(s):  
Dion Brocks ◽  
Hamdah Al Nebaihi ◽  
Shamima Parvin ◽  
Amel Hamza
Keyword(s):  
Body Weight ◽  
Total Body Weight ◽  
Drug Clearance ◽  
Lean Body Weight ◽  
Adult Obesity ◽  
Metabolizing Enzymes ◽  
Comparative Pharmacokinetic ◽  
Liver And Kidney ◽  
Obese Subjects ◽  
Total Body

In many comparative trials examining the effects of adult obesity on pharmacokinetics of drugs, conclusions were made based on values that were either not adjusted to total body weight or adjusted to non-obese body mass (e.g., ideal or lean body weight). In many cases these values were higher in the obese subjects. We have reviewed the data from comparative human trials, and it is apparent that in examining clearance normalization to total body weight (as typically done in studies involving pediatric obese patients), the clearances are often reduced in the obese. We have also reviewed the results of experimental obese versus non-obese rodent models. Those studies have mostly found that the systemic exposures to the same dose per body weight are increased, with obesity-related decreases in clearance. Furthermore, the expression of a number of important drug metabolizing enzymes are reduced in the experimental obese state. There is also evidence that obesity causes increases in the measured mass of eliminating organs such as liver and kidney. Human clearance normalized to total body weight appears to better reflect the underlying changes reported in the expression of protein and functional activity of drug clearance mechanisms.  

scholarly journals Lean body weight versus total body weight to calculate the iodinated contrast media volume in abdominal CT: a randomised controlled trial

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Moreno Zanardo ◽  
Fabio Martino Doniselli ◽  
Anastassia Esseridou ◽  
Massimiliano Agrò ◽  
Nicol Antonina Rita Panarisi ◽  
...  
Keyword(s):  
Body Weight ◽  
Contrast Media ◽  
Controlled Trial ◽  
Total Body Weight ◽  
Lean Body Weight ◽  
Iodinated Contrast Media ◽  
Abdominal Ct ◽  
Iodinated Contrast ◽  
Significant Difference ◽  
Total Body

Abstract Objectives Iodinated contrast media (ICM) could be more appropriately dosed on patient lean body weight (LBW) than on total body weight (TBW). Methods After Ethics Committee approval, trial registration NCT03384979, patients aged ≥ 18 years scheduled for multiphasic abdominal CT were randomised for ICM dose to LBW group (0.63 gI/kg of LBW) or TBW group (0.44 gI/kg of TBW). Abdominal 64-row CT was performed using 120 kVp, 100–200 mAs, rotation time 0.5 s, pitch 1, Iopamidol (370 mgI/mL), and flow rate 3 mL/s. Levene, Mann–Whitney U, and χ2 tests were used. The primary endpoint was liver contrast enhancement (LCE). Results Of 335 enrolled patients, 17 were screening failures; 44 dropped out after randomisation; 274 patients were analysed (133 LBW group, 141 TBW group). The median age of LBW group (66 years) was slightly lower than that of TBW group (70 years). Although the median ICM-injected volume was comparable between groups, its variability was larger in the former (interquartile range 27 mL versus 21 mL, p = 0.01). The same was for unenhanced liver density (IQR 10 versus 7 HU) (p = 0.02). Median LCE was 40 (35–46) HU in the LBW group and 40 (35–44) HU in the TBW group, without significant difference for median (p = 0.41) and variability (p = 0.23). Suboptimal LCE (< 40 HU) was found in 64/133 (48%) patients in the LBW group and 69/141 (49%) in the TBW group, but no examination needed repeating. Conclusions The calculation of the ICM volume to be administered for abdominal CT based on the LBW does not imply a more consistent LCE.

P0264ASSESSMENT OF GFR IN MORBIDLY OBESE PATIENTS USING DIFFERENT EQUATIONS: WHICH IS THE BEST?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Alaa Sabry ◽  
Amir Basiony ◽  
Mohamed Kamal
Keyword(s):  
Body Weight ◽  
Creatinine Clearance ◽  
Glomerular Filtration ◽  
Total Body Weight ◽  
Lean Body Weight ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Morbidly Obese Patient ◽  
Gault Formula ◽  
Total Body

Abstract Background and Aims Obesity is a potent risk factor for the development of kidney disease. The prevalence of abdominal obesity in Egyptians based upon the European cut-off points was 30.2% for men and 70.9% for women. To detect the best formula for estimation of glomerular filtration rates in morbidly obese individuals. Method: In this prospective study 82 morbidly obese patients were included, Age: 15 to 65 years, Morbidly obese patient (BMI &gt; 40 Kg/m2), Creatinine clearance calculated from a 24-h urine was done, Estimated glomerular filtration rate (eGFR): It was assessed to be correlated with creatinine clearance and detect the most suitable formula for morbidly obese patients. Cockcroft-Gault formula:  Cockcroft-Gault formula (for total body weight): ockcroft-Gault formula (for adjusted body weight): Cockcroft-Gault formula (for lean body weight), MDRD-eGFR (Modification of Diet in Renal Disease equation) (Shahbaz & Gupta, 2019), CKD-epidemiology (CKD-EPI): (Levey, et al, 2009) Results Demogrphic criteria of the studdied patients Conclusion: The equations that had the nearest values to creatinine clearance were CG-TBW-GFR and CGAjBW- GFR, both of them had a moderate reliability with more agreement for the CG-TBW-GFR equation . The CG-TBW-GFR formula was the most reliable one to measure GFR, followed by the CG-AjBW-GFR formula, while the CG-IBW, CG-LBW, MDRD-GFR and CKD-EPI-GFR formulae were not reliable at all .

scholarly journals Comparative study of anaesthesia induction in obese dogs using propofol dosages based on lean body weight or total body weight

2020 ◽  
Vol 10 ◽  
pp. 100131
Author(s):  
Fernanda Corrêa Devito ◽  
Geni Cristina Fonseca Patricio ◽  
Patrícia Bonifácio Flôr ◽  
Thiago Henrique Annibale Vendramini ◽  
Andressa Rodrigues Amaral ◽  
...  
Keyword(s):  
Body Weight ◽  
Comparative Study ◽  
Total Body Weight ◽  
Lean Body Weight ◽  
Anaesthesia Induction ◽  
Total Body

INFLUENCE OF DIET COMPOSITION AND CALORIC INTAKE ON BODY WEIGHT OF WARM- AND COLD-ACCLIMATED RATS

1963 ◽  
Vol 41 (1) ◽  
pp. 2225-2235
Author(s):  
A. DesMarais ◽  
P. A. Lachance
Keyword(s):  
Body Weight ◽  
Body Fat ◽  
Total Body Weight ◽  
Lean Body Weight ◽  
High Fat ◽  
High Carbohydrate ◽  
Exposure To Cold ◽  
Total Body Fat ◽  
Ad Libitum ◽  
Total Body

The well known reduction in growth rate of cold-acclimated rats has been shown to depend on a decreased gain in total body fat, without change in the gain in lean body weight. This has been observed in rats fed Lab Chow or a high-fat diet ad libitum. In those groups fed a high-carbohydrate diet ad libitum or calorie-restricted high-fat or high-carbohydrate diets, exposure to cold had no effect on the gain in neither total body weight nor lean body weight, which were already reduced by the diet; in those animals, the significant decrease in the gain in total body fat upon exposure to cold was compensated by a slight but unsignificant increase in the gain in lean body weight, so that differences in gain in total body weight were not significant.

scholarly journals The expression of growth-arrest genes in the liver and kidney of the protein-restricted rat fetus

2005 ◽  
Vol 94 (1) ◽  
pp. 12-18 ◽  
Author(s):  
Christopher A. Maloney ◽  
Christina Lilley ◽  
Morven Cruickshank ◽  
Caroline McKinnon ◽  
Susan M. Hay ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Body Weight ◽  
Kinase Inhibitors ◽  
Fetal Liver ◽  
Growth Arrest ◽  
Total Body Weight ◽  
Low Protein ◽  
Liver And Kidney ◽  
Steady State Levels ◽  
Total Body

During fetal life, there are periods of rapid cell proliferation, which are uniquely sensitive to nutritional perturbation. Feeding the pregnant rat a protein-restricted diet alters the growth trajectory of major fetal organs such as the kidney. By day 21 of gestation, the ratio of kidney weight to total body weight is reduced in the fetuses of dams fed a protein-deficient diet. In contrast, the ratio of fetal liver weight to total body weight is unchanged. To investigate the mechanisms underlying this disproportionate change in organ growth in the low-protein group, cell proliferation and differentiation have been assessed in the liver and kidney. The steady-state levels of mRNA for the growth-arrest and DNA-damage genegadd153/CHOP-10, CCAAT enhancer-binding proteins α and β were unaffected by maternal diet in both fetal liver and kidney. The mRNA for alpha-fetoprotein, albumin and hepatic glucokinase were unchanged in the liver, suggesting that maternal protein deficiency does not alter the state of differentiation. The steady-state levels of the mRNA coding for the cyclin-dependent protein kinase inhibitors (p15INK4a, p19INK4d, p21CIP1, p27KIP1and p57KIP2) were unchanged in the fetal livers but were significantly increased in the kidneys of fetuses from dams fed the low-protein diet. These results show that the asymmetrical growth of the kidney is associated with increases in mRNA for the Cip/Kip cyclin-dependent kinase inhibitors and that these may reflect specific lesions in organ development.

scholarly journals Towards Personalised Contrast Injection: Artificial-Intelligence-Derived Body Composition and Liver Enhancement in Computed Tomography

2021 ◽  
Vol 11 (3) ◽  
pp. 159
Author(s):  
Daan J. de Jong ◽  
Wouter B. Veldhuis ◽  
Frank J. Wessels ◽  
Bob de Vos ◽  
Pim Moeskops ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Computed Tomography ◽  
Body Mass Index ◽  
Body Weight ◽  
Body Mass ◽  
Total Body Weight ◽  
Lean Body Weight ◽  
Contrast Enhanced ◽  
Total Body ◽  
Enhanced Computed Tomography

In contrast-enhanced computed tomography, total body weight adapted contrast injection protocols have proven successful in achieving a homogeneous enhancement of vascular structures and liver parenchyma. However, because solid organs have greater perfusion than adipose tissue, the lean body weight (fat-free mass) rather than the total body weight is theorised to cause even more homogeneous enhancement. We included 102 consecutive patients who underwent a multiphase abdominal computed tomography between March 2016 and October 2019. Patients received contrast media (300 mgI/mL) according to bodyweight categories. Using regions of interest, we measured the Hounsfield unit (HU) increase in liver attenuation from unenhanced to contrast-enhanced computed tomography. Furthermore, subjective image quality was graded using a four-point Likert scale. An artificial intelligence algorithm automatically segmented and determined the body compositions and calculated the percentages of lean body weight. The hepatic enhancements were adjusted for iodine dose and iodine dose per total body weight, as well as percentage lean body weight. The associations between enhancement and total body weight, body mass index, and lean body weight were analysed using linear regression. Patients had a median age of 68 years (IQR: 58–74), a total body weight of 81 kg (IQR: 73–90), a body mass index of 26 kg/m2 (SD: ±4.2), and a lean body weight percentage of 50% (IQR: 36–55). Mean liver enhancements in the portal venous phase were 61 ± 12 HU (≤70 kg), 53 ± 10 HU (70–90 kg), and 53 ± 7 HU (≥90 kg). The majority (93%) of scans were rated as good or excellent. Regression analysis showed significant correlations between liver enhancement corrected for injected total iodine and total body weight (r = 0.53; p < 0.001) and between liver enhancement corrected for lean body weight and the percentage of lean body weight (r = 0.73; p < 0.001). Most benefits from personalising iodine injection using %LBW additive to total body weight would be achieved in patients under 90 kg. Liver enhancement is more strongly associated with the percentage of lean body weight than with the total body weight or body mass index. The observed variation in liver enhancement might be reduced by a personalised injection based on the artificial-intelligence-determined percentage of lean body weight.

scholarly journals A Large Impact of Obesity on the Disposition of Ivermectin, Moxidectin and Eprinomectin in a Canine Model: Relevance for COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Alain Bousquet-Mélou ◽  
Anne Lespine ◽  
Jean-François Sutra ◽  
Isabelle Bargues ◽  
Pierre-Louis Toutain
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Obese Subject ◽  
Control Period ◽  
Total Body Weight ◽  
Canine Model ◽  
Volume Of Distribution ◽  
Lean Body Weight ◽  
Total Body

Ivermectin (IVM) and moxidectin (MOX) are used extensively as parasiticides in veterinary medicine. Based on in vitro data, IVM has recently been proposed for the prevention and treatment of COVID-19 infection, a condition for which obesity is a major risk factor. In patients, IVM dosage is based on total body weight and there are no recommendations to adjust dosage in obese patients. The objective of this study was to establish, in a canine model, the influence of obesity on the clearance and steady-state volume of distribution of IVM, MOX, and a third analog, eprinomectin (EPR). An experimental model of obesity in dogs was based on a high calorie diet. IVM, MOX, and EPR were administered intravenously, in combination, to a single group of dogs in two circumstances, during a control period and when body weight had been increased by 50%. In obese dogs, clearance, expressed in absolute values (L/day), was not modified for MOX but was reduced for IVM and EPR, compared to the initial control state. However, when scaled by body weight (L/day/kg), plasma clearance was reduced by 55, 42, and 63%, for IVM, MOX and EPR, respectively. In contrast, the steady-state volume of distribution was markedly increased, in absolute values (L), by obesity. For IVM and MOX, this obese dog model suggests that the maintenance doses in the obese subject should be based on lean body weight rather than total weight. On the other hand, the loading dose, when required, should be based on the total body weight of the obese subject.

scholarly journals Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

2012 ◽  
Vol 57 (3) ◽  
pp. 1144-1149 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Pavlos K. Papasavas ◽  
Darren S. Tishler ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Body Weight ◽  
Ideal Body Weight ◽  
Total Body Weight ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Lean Body Weight ◽  
Morbidly Obese ◽  
Total Body ◽  
Nonobese Patients

ABSTRACTThe pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m2receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (K12andK21) of 8.04 ± 6.22 and 7.99 ± 5.46 h−1, respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 μg · h/ml (P= 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r2= 0.524), adjusted body weight (r2= 0.587), lean body weight (r2= 0.495), and ideal body weight (r2= 0.398), but not with BMI (r2= 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.

scholarly journals Large Impact of obesity on the disposition of ivermectin, moxidectin and eprinomectin in a canine model: relevance for COVID-19 patients.

2021 ◽  
Author(s):  
Alain Bousquet-Melou ◽  
Anne Lespine ◽  
Jean-François Sutra ◽  
Isabelle Bargues ◽  
Pierre Louis Toutain
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Obese Subject ◽  
Control Period ◽  
Total Body Weight ◽  
Canine Model ◽  
Volume Of Distribution ◽  
Lean Body Weight ◽  
Total Body

Background and Purpose: Based on in vitro data, ivermectin (IVM) has been proposed for the prevention and treatment of COVID-19, a condition for which obesity is a major risk factor. IVM dosage is based on total body weight and there are no recommendations to adjust dosage in obese patients. The objective of this study was to establish, in a canine model, the influence of obesity on the clearance and steady-state volume of distribution of IVM and two analog compounds, moxidectin (MOX) and eprinomectin (EPR). Experimental Approach: An experimental model of obesity in dogs was based on a high calorie diet. IVM, MOX and EPR were administered intravenously, simultaneously in combination, to a single group of dogs in two circumstances, during a control period and when body weight had been increased by 50%. Key Results: In obese dogs, clearance, expressed in absolute values (L/day), was not modified for MOX and reduced for IVM and EPR, compared to the initial control state. When scaled by body weight (L/day/kg), plasma clearance was reduced by 42, 55 and 63%, for MOX, IVM and EPR, respectively. In contrast, the steady-state volume of distribution was markedly increased in absolute values (L) by obesity. Conclusion and Implications: For IVM and MOX, the obese dog model suggests that the maintenance dose should not be adjusted by total body weight in the obese subject but should be based on lean body weight. On the other hand, the loading dose should be computed based on the total body weight of the obese subject.

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