Impact of Obesity on Hepatic Drug Clearance: What are the Influential Variables?
allometric scaling
hepatic metabolism
obesity
physiological-based pharmacokinetics
Journal
The AAPS journal
ISSN: 1550-7416
Titre abrégé: AAPS J
Pays: United States
ID NLM: 101223209
Informations de publication
Date de publication:
09 May 2024
09 May 2024
Historique:
received:
20
02
2024
accepted:
24
04
2024
medline:
10
5
2024
pubmed:
10
5
2024
entrez:
9
5
2024
Statut:
epublish
Résumé
Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index [BMI] = 20) and subjects with various severities of obesity (BMI 25-60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m
Identifiants
pubmed: 38724865
doi: 10.1208/s12248-024-00929-3
pii: 10.1208/s12248-024-00929-3
doi:
Substances chimiques
Pharmaceutical Preparations
0
Orosomucoid
0
Serum Albumin, Human
ZIF514RVZR
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
59Informations de copyright
© 2024. The Author(s).
Références
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