Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

Rongen, Anne van; Brill, Margreke J. E.; Vaughns, Janelle D.; Välitalo, Pyry A. J.; Dongen, Eric P.A. van; Ramshorst, Bert van; Barrett, Jeffrey S.; Anker, Johannes N. van den; Knibbe, Catherijne A. J.

doi:10.1007/s40262-017-0579-4

Cited by 29 publications

(34 citation statements)

References 47 publications

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“…Lipophilic substances then have a larger volume of distribution and consequently a lower clearance. Bioavailability is also increased (Brill et al, 2014), possibly due to obesity-induced suppression of CYP3A activity (Brill et al, 2015;van Rongen et al, 2018).…”

Section: Role Of Obesitymentioning

confidence: 99%

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use

Gougis

Funck‐Brentano

Paci

et al. 2019

Critical Reviews in Oncology/Hematology

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Protein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over-or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed.

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Section: Role Of Obesitymentioning

confidence: 99%

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use

Gougis

Funck‐Brentano

Paci

et al. 2019

Critical Reviews in Oncology/Hematology

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“…A recent population pharmacokinetic modeling analysis of midazolam found that midazolam clearance in morbidly obese adults was not predictive of clearance in obese adolescents. 94 Clinical studies typically do not collect and/or report duration of obesity, but this may be a variable of importance, for example, to compare similarity at baseline of demography in the treatment groups. More research is needed on drug transporters, drug-metabolizing enzymes, and their polymorphisms in both youth and adults to better predict how drug disposition and metabolism are affected along the spectrum of obesity, compounded over time with the accumulation of obesity comorbidities.…”

Section: Nonobesity Drugs Used In Hospitalized Pediatric Patientsmentioning

confidence: 99%

Pediatric Obesity: Influence on Drug Dosing and Therapeutics

Ameer

Weintraub

2018

The Journal of Clinical Pharma

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Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of U.S. children and adolescents. Severe obesity (≥120% of the 95th percentile of body mass index (BMI) for age, or a BMI ≥ 35 kg/m2) is the fastest‐growing subgroup and now approaches 6% of all U.S. youth. Health consequences (eg, type 2 diabetes, coronary heart disease) are related in a dose‐dependent manner to severity of obesity. Because therapeutic interventions are less effective in severe obesity, prevention is a high priority. Treatment plans involving combinations of behavioral therapy, nutrition, and exercise achieve limited success. Only one drug, orlistat, is U.S. Food and Drug Administration approved for long‐term obesity management in adolescents 12 years and older. As part of comprehensive medication management, clinicians should consider the propensity for a given drug to aggravate weight gain and to consider alternatives that minimize weight impact. Medication management must take into account developmental changes as well as the pathophysiology of obesity and comorbidities. Despite expanding insight into obesity pathophysiology, there are gaps in its translation to therapeutic application. The historical construct of obesity as simply a fat‐storage disorder is fundamentally inaccurate. The approach to adjusting doses based solely on body size and extrapolating from therapeutic knowledge of adult obesity may be based on assumptions that are not fully substantiated. Classes of drugs commonly prescribed for comorbidities associated with obesity should be prioritized for clinical research evaluations aimed at optimizing dosing regimens in pediatric obesity.

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“…Some common target‐controlled infusion pumps deliver propofol using LBM for obese adults despite knowledge that propofol clearance is better calculated using TBM with allometric scaling . Dosing of midazolam in adolescents presenting for bariatric surgery remains problematic because of the lack of clear guidance for quantifying excess weight and using this to calculate the dose …”

Section: Current Dosing Regimens For Obese Childrenmentioning

confidence: 99%

“…11,12 Dosing of midazolam in adolescents presenting for bariatric surgery remains problematic because of the lack of clear guidance for quantifying excess weight and using this to calculate the dose. 13,14 3 | EMPIRICAL LINKS BETWEEN WE IGHT…”

Section: Cur Rent D Osin G Regimens For Obese Childrenmentioning

confidence: 99%

What is the best size predictor for dose in the obese child?

Anderson

Holford

2017

Pediatric Anesthesia

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SummaryLean body mass is commonly proposed for anesthesia maintenance drug dosing calculations. However, total body mass used with allometric scaling has been shown to be better for propofol in obese adults and children. Fat-free mass has also been used instead of lean body mass. Fat-free mass is essentially the same as lean body mass but excludes a small percentage of mass of lipids in cell membranes, CNS, and bone marrow. Normal fat mass is a size descriptor that partitions total body mass into fat-free mass and fat mass calculated from total body mass minus fat-free mass.The relative influence of fat mass compared with fat-free mass is described by the fraction of fat mass that makes fat equivalent to fat-free mass in terms of allometric size. This fraction (Ffat) will differ for each drug and each parameter affected by body size (eg, clearance and volume of distribution). This fraction is based on the concept of theory-based allometric size. The normal fat mass based on allometric theory and partition of body mass into fat and fat-free components provides a principle-based approach explaining size and body composition effects on pharmacokinetics of all drugs in children and in adults. 1 This speculation is difficult to test because of the well-known biologically driven relationship between body structure and function driven by body mass. 2 In order to evaluate the influence of obesity, it is necessary to find a means to distinguish between size and the independent effects of obesity.We have proposed using a theory-based relationship between body mass and size-related differences in clearance to distinguish between size and age-related effects in early life that reflect maturation of organ function. 3 This approach has proved useful for describing glomerular filtration rate and clearance of many drugs. 4We have also suggested using a similar theory-based approach to distinguish the influence of fat and fat-free components of body mass used to predict clearance and volume of distribution. 5 In this review, we expand on these concepts to develop a framework for determining if there is an influence of obesity on pharmacokineticparameters. We also demonstrate how pharmacokinetic parameters may be predicted using fat mass with application to drug dosing in children and adults.

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Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

Cited by 29 publications

References 47 publications

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use

Pediatric Obesity: Influence on Drug Dosing and Therapeutics

What is the best size predictor for dose in the obese child?

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