The impact of obesity on the pharmacokinetics of drugs in adolescents and adults

  Despite the increasing number of obese patients, evidence-based dosing guidelines are scarce, particularly for obese children and morbidly obese adults (BMI > 40 kg/m2). For both these populations, pharmacokinetic studies are needed to provide a basis for evidence-based dosing guidelines. In this thesis, we studied the pharmacokinetics of the CYP3A substrate midazolam, the renally excreted drug metformin and acetaminophen (metabolized by glucuronidation, sulphation and CYP2E1) in obese adolescents and/or morbidly obese adults. We address several currently unanswered questions; Can doses for obese adolescents be predicted on the basis of data obtained in morbidly obese adults? How to analyse pharmacokinetic data in obese adolescents, for whom body weight is influenced by growth, age and obesity? How to achieve safe and effective acetaminophen dosing for morbidly obese patients? The studies described in this thesis contribute to the existing gaps in knowledge regarding the pharmacokinetics and evidence-based dosing of drugs in obese adolescents and morbidly obese adults.  Department of Clinical Pharmacy, St. Antonius Hospital Department of Anaesthesiology and Intensive Care, St. Antonius HospitalPharmacolog

Individualized dosing of evinacumab is predicted to yield reductions in drug expenses

Background: Evinacumab is a first-in-class inhibitor of angiopoietin‐like protein 3 (ANGPTL3) for treatment of the rare disease homozygous familial hypercholesterolemia (HoFH). With projected drug costs of $450,000 per person per year, the question rises if cost-efficacy of evinacumab can be further improved. Objectives: To develop an individualized dosing regimen te reduce drug expenses. Methods: Using the clinical and pharmacological data as provided by the license holder, we developed an alternative dosing regimen in silico based on the principles of reduction of wastage by dosing based on weight bands rather than a linear milligram per kilogram body weight (mg/kg) dosing regimen, as well as dose individualization guided by low density lipoprotein cholesterol (LDL-C) response. Results: We found that the average quantity of drug used for a dose could be reduced by 34% without predicted loss in efficacy (LDL-C reduction 24 weeks after treatment initiation). Conclusion: Dose reductions without compromising efficacy seem feasible. We call for implementation and prospective evaluation of this strategy to reduce treatment costs of HoFH.</p

Mateship and Money-Making: Shearing in Twentieth Century Australia

After the turmoil of the 1890s shearing contractors eliminated some of the frustration from shearers recruitment. At the same time closer settlement concentrated more sheep in small flocks in farming regions, replacing the huge leasehold pastoral empires which were at the cutting edge of wool expansion in the nineteenth century. Meanwhile the AWU succeeded in getting an award for the pastoral industry under the new arbitration legislation in 1907. Cultural and administrative influences, therefore, eased some of the bitter enmity which had made the annual shearing so unstable. Not all was plain sailing. A pattern of militancy re-emerged during World War I. Shearing shed unrest persisted throughout the interwar period and during World War II. In the 1930s a rival union with communist connections, the PWIU, was a major disruptive influence. Militancy was a factor in a major shearing strike in 1956, when the boom conditions of the early-1950s were beginning to fade. The economic system did not have satisfactory mechanisms to cope. Unionised shearers continued to be locked in a psyche of confrontation as wool profits eroded further in the 1970s. This ultimately led to the wide comb dispute, which occurred as wider pressures changed an economic order which had not been seriously challenged since Federation, and which the AWU had been instrumental in shaping. Shearing was always identified with bushworker ‘mateship’, but its larrikinism and irreverence to authority also fostered individualism, and an aggressive ‘moneymaking’ competitive culture. Early in the century, when old blade shearers resented the aggressive pursuit of tallies by fast men engaged by shearing contractors, tensions boiled over. While militants in the 1930s steered money-makers into collectivist versions of mateship, in the farming regions the culture of self-improvement drew others towards the shearing competitions taking root around agricultural show days. Others formed their own contracting firms and had no interest in confrontation with graziers. Late in the century New Zealanders arrived with combs an inch wider than those that had been standard for 70 years. It was the catalyst for the assertion of meritocracy over democracy, which had ruled since Federation

How needs and preferences of employees influence participation in health promotion programs: A six-month follow-up study

Background: Low participation in health promotion programs (HPPs) might hamper their effectiveness. A potential reason for low participation is disagreement between needs and preferences of potential participants and the actual HPPs offered. This study aimed to investigate employees' need and preferences for HPPs, whether these are matched by what their employers provide, and whether a higher agreement enhanced participation. Methods: Employees of two organizations participated in a six-month follow-up study (n = 738). At baseline, information was collected on employees' needs and preferences for the topic of the HPP (i.e. physical activity, healthy nutrition, smoking cessation, stress management, general health), whether they favored a HPP via their employer or at their own discretion, and their preferred HPP regarding three components with each two alternatives: mode of delivery (individual vs. group), intensity (single vs. multiple meetings), and content (assignments vs. information). Participation in HPPs was assessed at six-month

Barriers and facilitators for participation in health promotion programs among employees: A six-month follow-up study

Background: Health promotion programs (HPPs) are thought to improve health behavior and health, and their effectiveness is increasingly being studied. However, participation in HPPs is usually modest and effect sizes are often small. This study aims to (1) gain insight into the degree of participation of employees in HPPs, and (2) identify factors among employees that are associated with both their intention to participate and actual participation in HPPs. Methods. Employees of two organizations were invited to participate in a six-month follow-up study (n = 744). Using questionnaires, information on participation in HPPs was collected in two categories: employees' intention at baseline to participate and their actual participation in a HPP during the follow-up period. The following potential determinants were assessed at baseline: social-cognitive factors, perceived barriers and facilitators, beliefs about health at work, health behaviors, and self-perceived health. Logistic regression analyses, adjusted for demographics and organization, were used to examine associations between potential determinants and intention to participate, and to examine the effect of these determinants on actual participation during follow-up. Results: At baseline, 195 employees (26%) expressed a positive intention towards participation in a HPP. During six months of follow-up, 83 employees (11%) actually participated. Participants positively inclined at baseline to participate in a HPP were more likely to actually participate (OR = 3.02, 95% CI: 1.88-4.83). Privacy-related barriers, facilit

An INDEHISCENT-controlled auxin response specifies the separation layer in early Arabidopsis fruit

Plant science

Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

Background The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. Methods Data from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor age and length) was evaluated. Results The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed. Discussion We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents