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

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.

Visualising the nutritional performance landscapes for the black soldier fly, Hermetia illucens (Diptera: Stratiomyidae)

The black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), has become one of the most economically important insects that can be a sustainable replacement for traditional feed for swine, poultry, and aquaculture. Despite its emerging importance, studies examining the nutritional requirement of BSF have been scarce. Here we used nutritional geometry approach to determine the separate and combined effects of dietary protein and carbohydrate content on multiple life-history traits and body composition linked to fitness in BSF. BSF larvae were reared on one of 32 chemically defined diets that varied in protein-to-carbohydrate ratio (P:C=1:16, 1:8, 1:4, 1:2, 1:1, 2:1, 4:1, or 8:1) and in protein plus carbohydrate concentration (P+C=60, 120, 180, or 240 g/l). Females developed more slowly into larger adults than males, but two sexes responded to dietary variation in protein and carbohydrate in a similar manner. The topography of the nutritional performance landscapes mapped for all measured traits differed significantly from one another, with the optimal P:C ratio being 1:1.71 for preadult survivorship, 1:1.56 – 1:1.11 for development time, 1:3.36 – 1:3.16 for body weight at adult emergence, and 1:1.83 – 1:1.40 for growth rate. Significant divergence in nutritional optima among these components of fitness indicates that the occurrence of fundamental life-history trade-off can be mediated by macronutrient intake. The index representing the preadult performance of BSF had a nonlinear relationship with dietary protein, with the peak centred at the intermediate P:C ratios of 1:1.43 – 1:1.37. The optimal P:C ratio was 1:2.12 – 1:1.70 for lean body weight and 1:14.14 – 1:10.82 for lipid content. Our results highlight the importance of the balanced composition of dietary protein and carbohydrate for optimising BSF performance and have implications for enhancing the mass production of this beneficial species.

Evaluation and enhancement of standard equations for renal function estimation in individuals with components of metabolic disease

Background The primary objective of this study aims to test patient factors, with a focus on cardiometabolic disease, influencing the performance of the Cockcroft-Gault equation in estimating glomerular filtration rate. Methods A cohort study was performed using data from adult patients with both a 24-h urine creatinine collection and a serum creatinine available. Creatinine clearance was calculated for each patient using the Cockcroft-Gault, Modified Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations and estimates were compared to the measured 24-h urine creatinine clearance. In addition, new prediction equations were developed. Results In the overall study population (n = 484), 44.2% of patients were obese, 44.0% had diabetes, and 30.8% had dyslipidemia. A multivariable model which incorporating patient characteristics performed the best in terms of correlation to measured 24-h urine creatinine clearance, accuracy, and error. The modified Cockcroft-Gault equation using lean body weight performed best in the overall population, the obese subgroup, and the dyslipidemia subgroup in terms of strength of correlation, mean bias, and accuracy. Conclusions Regardless of strategy used to calculate creatinine clearance, residual error was present suggesting novel methods for estimating glomerular filtration rate are urgently needed.

Development and validation of a length- and habitus-based method of ideal and lean body weight estimation for critically ill adults requiring urgent weight-based medical intervention

Objective: Accurate drug dosing in obese patients requires an estimation of ideal body weight (IBW) or lean body weight (LBW) for dosing hydrophilic medications. Erroneous weight estimates during the management of critically ill adults may contribute to poor outcomes. Existing methods of IBW and LBW estimation or measurement are very difficult to use during emergency care. A new point-of-care model is needed to provide rapid estimates of IBW and LBW for this purpose. Methods A model was derived based on the PAWPER XL-MAC tape, a pediatric weight estimation system, which uses recumbent length and mid-arm circumference to estimate IBW and LBW. The model was used to generate weight estimations in a derivation sample (n=33155) and a validation sample (n=5926) from National Health and Nutrition Examination Survey (NHANES) datasets. The outcome measure was to achieve >95% of IBW and LBW estimations within 20% of recognized reference standards (P20>95%) and >70% of estimations within 10% of these standards (P10>70%). Main Results: The new model achieved a P20 of 100% and a P10 of 99.9% for IBW and a P20 of 98.3% and a P10 of 78.3% for LBW. This accuracy was maintained in both sexes, all ages, all ethnic groups, all lengths and in all habitus-types, except for the morbidly obese female subgroup. Conclusions The modified PAWPER XL-MAC model proved to be an accurate method of IBW and LBW estimation. It could, therefore, have an important role in facilitating emergency drug dose calculations in acutely or critically ill obese adult patients. Conclusions The modified PAWPER XL-MAC model proved to be an accurate method of IBW and LBW estimation. It could, therefore, have an important role in facilitating emergency drug dose calculations in acutely or critically ill obese adult patients.

Differences between Active and Semi-Active Students Regarding the Parameters of Body Composition Using Bioimpedance and Magnetic Bioresonance Technologies

The aim of the study was to identify differences in obesity-related parameters between active sports students and semi-active or sedentary students, differentiated by sex, in order to optimize health. The study sample included 286 students, of which the male experimental sample consisted of 86 active sports students, age X ± SD 21.25 ± 0.32 years; height X ± SD 181.08 ± 3.52 cm; control group consisting of 89 semi-active students aged X ± SD 21.07 ± 0.1.13 years; height X ± SD 182.11 ± 1.32. The female experimental sample includes 57 active sports students, age X ± SD 21.02 ± 0.92 years; height X ± SD 167.48 ± 1.34 cm; the control group includes 54 semi-active students aged X ± SD 21.57 ± 0.1.98 years; height X ± SD 168.42 ± 1.76. The study used a thalliometer, Tanita Health Ware software and Quantum Resonance Magnetic Analyzer equipment to investigate height (cm), Body Mass Index (BMI), muscle mass (kg, %), as well as the obesity analysis report, and componential analysis of body and nourishment. The differences registered between the samples of active and semi-active sports subjects were predominantly statistically significant for p < 0.05. The differences registered between the samples of active and semi-active sports subjects were predominantly statistically significant for p < 0.05. The most important parameters regarding obesity and body composition that registered significant differences between the two male groups were in favor of the group of active athletes: triglyceride content of abnormal coefficient 0.844 (CI95% 0.590–1.099), abnormal lipid metabolism coefficient 0.798 (CI95% 1.091–0.504), obesity degree of body (ODB %) 10.290 (CI95% 6.610–13.970), BMI 2.326 (CI95% 1.527–3.126), body fat (kg) 2.042 (CI95% 0.918–3.166), muscle volume (kg) 2.565 (CI95% 1.100–4.031), Lean body weight (kg) 2.841 (CI95% 5.265–0.418). In the case of female samples, the group of active sportswomen registered the biggest differences compared to the group of students who were significantly active in the parameters: abnormal lipid metabolism coefficient 1.063 (CI95% 1.380–0.746), triglyceride content of abnormal coefficient 0.807 (CI95% 0.437–1.178), obesity degree of body (ODB%) 8.082 (CI95% 2.983–13.181), BMI 2.285 (CI95% 1.247–3.324), body fat (kg) 2.586 (CI95% 0.905–4.267), muscle volume (kg) 2.570 (CI95% 0.154–4.985), lean body weight (kg) 4.118 (CI95% 1.160–7.077). The results of the study directly facilitate the understanding of the complexity of the impact of obesity on multiple parameters of body composition and health.

Does Contrast Dose Based in Lean body Weight Allow Lesser Volumes on High BMI Patients for CT Angiography?

Objectives: The objective was to evaluate whether contrast dose based on lean body weight (LBW) protocol has the potential to reduce contrast volume in patients with high basal metabolic index (BMI) compared to total body weight (TBW)-based protocols. Material and Methods: The Institutional Review Board approval was obtained for this prospective study. Initially, a pilot study with a sample size of 150 patients was conducted to estimate the average fat fraction in our population. Then, CT angiography (CTA) for the thoracic and abdominal aorta was performed using a 256-multidetector computed tomography scanner in 117 patients who were undergoing screening for aortic aneurysm and vascular assessment of prospective transplant donors. The patients were divided into two groups: A TBW group (n = 60) and LBW group (n = 57). Lean body weight (LBW) was estimated from the patient weight, height, and gender using Hume’s equation. The TBW group received 1.2 ml/kg contrast dose and the LBW group received 1.6 ml/kg contrast dose to achieve approximately equal iodine dose in both groups. Differences in the degree of aortic enhancement between the estimated LBW and TBW group were evaluated. In higher BMI patients (>25), the mean aortic enhancement (MAEnh) and the contrast volume delivered between the LBW and TBW group were compared. Results: Mean aortic enhancement (MAEnh) 422.45 (±74.5) Hounsfield unit (HU) in the TBW group and 432.67 (±69.4) HU in the LBW group showed no statistical difference (P = 0.439). In population with BMI >25, the contrast delivered in LBW protocol patients was significantly less (P = 0.00) compared to TBW protocol patients, with no significant difference in the MAEnh between the groups (P = 0.479). Conclusion: CTA using a LBW protocol helps to significantly reduce the volume of contrast delivered, especially in patients with BMI >25 compared to TBW protocol, without compromising the aortic enhancement.

Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

Purpose To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen. Methods Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression. Results SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest. Conclusion The approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

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

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.

Dosing of neuromuscular blocking agents in patients with obesity: A narrative review

There is no consensus on which weight clinicians should use for weight-based dosing of neuromuscular blocking agents (NMBAs), as exemplified by differing or absent recommendations in clinical practice guidelines. The purpose of this paper is to review studies that evaluated various size descriptors for weight-based dosing of succinylcholine and non-depolarising NMBAs, and to provide recommendations for the descriptors of choice for the weight-based dosing of these agents in patients with obesity. All of the studies conducted to date involving depolarising and non-depolarising NMBAs in patients with obesity have assessed single doses or short-term infusions conducted in perioperative settings. Recognising that any final dosing regimen must take into account patient-specific considerations, the available evidence suggests that actual body weight is the size descriptor of choice for weight-based dosing of succinylcholine and that ideal body weight, or an adjusted (or lean) body weight, is the size descriptor of choice for weight-based dosing of non-depolarising NMBAs.

Effect of Exercise and Weight Loss in Polycystic Ovarian Syndrome among Obese Women

Ovulation and fertility can be improved by weight loss in obese women with Polycystic Ovarian Syndrome (PCOS). The aim of this study was to investigate the effectiveness of a twelve-week supervised exercise program in combination with dietary restrictions for obese women with PCOS. The study is a quasi-experimental research and used an experimental pre- and post-test design. Fifteen women recruited from Fertility Clinic, Jessops Hospital for Women, Sheffield took part in this study. Respiratory exchange ratio (RER), heart rate, perceived exertion (RPE), and Houston non-exercise activity code were recorded. Height, weight, and body girth measurements were taken to calculate body mass index, fat percentage, and lean body weight. The intervention group lost an average of 3.1 kg and gained 3.45 kg of lean body weight. Loss of fat percentage was 12.1%. No significant difference was found in the control group. The RER and heart rate value decreased for the same workload in the intervention group, indicating higher tolerance towards exercise intensity. However, the changes for both groups were not significant. The average group compliance rate was 53% (at least two sessions per week). Bearing in mind the small sample size (n=4) for control, the improvement in fitness, significant weight loss, and body composition change (increase in fat-free mass) was achieved in this study. Twelve weeks of exercise, combined with dietary advice, were sufficient to benefit PCOS obese women. The research has achieved a commendable weight-loss objective and has demonstrated increases in standards of fitness among obese women.