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

Reflection paper on investigations of pharmacokinetics in

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https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-investigation-pharmacokinetics-obese-population-scientific-guideline_en.pdf

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Leptin, PD, Metabolism, Toxicity, Body composition, Ciprofloxacin, Clinical Pharmacokinetics, Water, LBW, Perfusion, LBM, Canadian International Council, AUC, PLOS One, Bariatric surgery, Clopidogrel, CYP, Breast, Health, DNA-binding protein, BMC Public Health, Pharmacology, BMI, CRP, Pharmaceutical Research (journal), Organ, Draft, Guideline, Bypass surgery, WHO, Ageing, INT, Pharmacokinetics, Liver, Bioavailability, Chronic liver disease, Human, Incidence, Committee, Absorption, TBW, Cardiovascular disease, Anatomy, CYP2C19, PBPK, Cmax, Factorization of polynomials, European, Lancet, CHMP, Journal, NASH, Pharmacotherapy, Adipose tissue, Non-alcoholic fatty liver disease, Journal of Clinical Investigation, Medication package insert, Overweight, NPS MedicineWise, Permeability, Benzodiazepine, Meta-analysis, Liver disease, Half-life, Acetylcholine, Ciclosporin, AAG, Kinetics, Midazolam, Kidney, Safety, Biomarker, Clinical Pharmacology & Therapeutics, Peptide, Classification, Hypertension, Metabolic syndrome, Acute coronary syndrome, Insulin resistance, Fatty liver disease, CYP2E1, Lithium, Body mass index, Reproduction, EMA, IBW, Injection, Anker, NCA, Enzyme, Inflammation, Cancer, Weight loss, Gastrointestinal tract, Cardiac output, Public health, Adipokine, CYP2C9, E pluribus unum, Physiology, Agency, Risk, Steroid, Lymph, CYP2D6, BSA, GI, Cytokine, Systematic review, Vaccine

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Summary

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

Page 2/12

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
Page 3/12

?

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
EMA/CHMP/535116/2016
Page 4/12

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
EMA/CHMP/535116/2016

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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
EMA/CHMP/535116/2016
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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
EMA/CHMP/535116/2016
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41.
Reflection paper on investigations of pharmacokinetics in the obese population
EMA/CHMP/535116/2016
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