biostudies-literatureTalkington AMNHLBI NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHS518-527https://www.ebi.ac.uk/biostudies/studies/S-EPMC9080587biostudies-literatureUnknown343PEGylation 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.Journal of controlled release : official journal of the Controlled Release SocietyA PBPK model recapitulates early kinetics of anti-PEG antibody-mediated clearance of PEG-liposomes.PMC9080587P30 CA016086R01 HL141934R35 GM119661T32 HL069768S10 OD023611Li ZZhang TLai SKFrank JECao YMcSweeney MDWessler TRath MKYuan HTalkington AMForest MGfalseA PBPK model recapitulates early kinetics of anti-PEG antibody-mediated clearance of PEG-liposomes.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.2022-01-01T00:00:00Z2022 Mar2026-06-04T04:59:55.81Z2025-04-04T08:52:55.123ZS-EPMC90805873506609910.1016/j.jconrel.2022.01.022