Reflection paper on investigation of pharmacokinetics in the obese population - Scientific guideline
Reflection paper on investigations of pharmacokinetics in
- Reflection paper on investigations of pharmacokinetics in
the obese population
Table of contents
1. - References .............................................................................................. 9
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1.
- This is considered
a shortcoming that is potentially compounded by obese patients often being poorly represented in
clinical studies. - The specific aims of this reflection paper are to:
?describe how the effects of obesity can be investigated during clinical medicinal product
development. - ?
provide recommendations on when investigations of the effect of obesity on the PK of a
medicinal product should be particularly considered. - Reflection paper on investigations of pharmacokinetics in the obese population
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?
discuss how to reflect PK (and/or PK/PD) findings in weight/weight-based dosing
recommendations. - Absorption
Reduced rate of absorption linked to locally reduced blood flow (8) is reported for the subcutaneous
and transdermal routes in obese subjects. - Distribution
The distribution of medicinal products is driven by body composition, regional blood flow and binding to
tissue and plasma proteins. - Obese subjects have a larger absolute lean body weight (LBW) as well as fat mass.
- The physicochemical properties of a medicinal product (lipophilicity, polarity, molecular size, and
degree of ionization) influence its distribution in the body. - In BMI class III obese
subjects, the blood flow per gram of fat is significantly lower than that observed in class I obese or
lean subjects (4). - Reflection paper on investigations of pharmacokinetics in the obese population
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An increased amount of alpha-1-acid-glycoprotein (AAG), linked to a chronic inflammatory state, is
reported in obese individuals. - Fatty infiltrations are present in the liver for 90% of obese subjects, with the extent of the infiltrations
being proportional to the degree of obesity. - In some cases, in particular for CYP3A4 metabolized medicinal products,
bodyweight normalized clearance can be lower in obese patients (23). - Based on presently available data, it has been suggested that uptake transporters
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are downregulated while efflux transporters may be upregulated (31).
- Platelet hyper-reactivity is also observed,
which can impair the response to anti-platelet medicinal products in obese patients (42, 43). - Reflection paper on investigations of pharmacokinetics in the obese population
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3.
the medicinal product properties and scientific literature indicate that obesity may lead to a
marked effect on elimination and/or distribution or on the PK/PD relationship. - These
models may aid in extrapolating the known efficacy and safety in the non-obese population to the
obese population. - The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients
Before and One Year After Bariatric Surgery. - Reflection paper on investigations of pharmacokinetics in the obese population
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41.
- Reflection paper on investigations of pharmacokinetics in the obese population
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