A PBPK model recapitulates early kinetics of anti-PEG antibody-mediated clearance of PEG-liposomes.
J Control Release
; 343: 518-527, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-35066099
ABSTRACT
PEGylation is routinely used to extend the systemic circulation of various protein therapeutics and nanomedicines. Nonetheless, mounting evidence is emerging that individuals exposed to select PEGylated therapeutics can develop antibodies specific to PEG, i.e., anti-PEG antibodies (APA). In turn, APA increase both the risk of hypersensitivity to the drug as well as potential loss of efficacy due to accelerated blood clearance of the drug. Despite the broad implications of APA, the timescales and systemic specificity by which APA can alter the pharmacokinetics and biodistribution of PEGylated drugs remain not well understood. Here, we developed a physiologically based pharmacokinetic (PBPK) model designed to resolve APA's impact on both early- and late-phase pharmacokinetics and biodistribution of intravenously administered PEGylated drugs. Our model accurately recapitulates PK and biodistribution data obtained from PET/CT imaging of radiolabeled PEG-liposomes and PEG-uricase in mice with and without APA, as well as serum levels of PEG-uricase in humans. Our work provides another illustration of the power of high-resolution PBPK models for understanding the pharmacokinetic impacts of anti-drug antibodies and the dynamics with which antibodies can mediate clearance of foreign species.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
/
Lipossomos
Limite:
Animals
Idioma:
En
Revista:
J Control Release
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos