Clinical Pharmacokinetics

Reflection paper on investigation of pharmacokinetics in the obese population - Scientific guideline

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수요일, 2월 14, 2024
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Reflection paper on investigations of pharmacokinetics in

Key Points: 
    • Reflection paper on investigations of pharmacokinetics in
      the obese population
      Table of contents
      1.
    • References .............................................................................................. 9

      Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

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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
      EMA/CHMP/535116/2016

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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

      Reflection paper on investigations of pharmacokinetics in the obese population
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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.
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      41.

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