PMID- 36949370 OWN - NLM STAT- MEDLINE DCOM- 20230601 LR - 20230601 IS - 1573-904X (Electronic) IS - 0724-8741 (Print) IS - 0724-8741 (Linking) VI - 40 IP - 5 DP - 2023 May TI - Mechanisms of Obesity-Induced Changes in Pharmacokinetics of IgG in Rats. PG - 1223-1238 LID - 10.1007/s11095-023-03496-y [doi] AB - PURPOSE: To evaluate how obesity affects the pharmacokinetics of human IgG following subcutaneous (SC) and intravenous (IV) administration to rats and the homeostasis of endogenous rat IgG. METHODS: Differences in body weight and size, body composition, and serum concentration of endogenous rat IgG in male Zucker obese (ZUC-FA/FA) and control (ZUC-LEAN) rats were measured from the age of 5 weeks up to 30 weeks. At the age of 23-24 weeks animals received a single IV or SC dose of human IgG (1 g/kg of total body weight), and serum pharmacokinetics was followed for 7 weeks. A mechanistic model linking obesity-related changes in pharmacokinetics with animal growth and changes in body composition was developed. RESULTS: Significant differences were observed in both endogenous and exogenous IgG pharmacokinetics between obese and control groups. The AUC for human IgG was lower in obese groups (57.6% of control after IV and 48.1% after SC dosing), and clearance was 1.75-fold higher in obese animals. The mechanistic population model successfully captured the data and included several major components: endogenous rat IgG homeostasis with age-dependent synthesis rate; competition of human IgG and endogenous rat IgG for FcRn binding and its effect on endogenous rat IgG concentrations following injection of a high dose of human IgG; and the effect of body size and composition (changing over time and dependent on the obesity status) on pharmacokinetic parameters. CONCLUSIONS: We identified important obesity-induced changes in the pharmacokinetics of IgG. Results can potentially facilitate optimization of the dosing of IgG-based therapeutics in the obese population. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Gao, Xizhe AU - Gao X AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. AD - Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Sheng, Yi-Hua AU - Sheng YH AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. AD - Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Yu, Sijia AU - Yu S AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. AD - Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Li, Jiadong AU - Li J AD - Comparative Medicine Resources, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Rosa, Raymond AU - Rosa R AD - Comparative Medicine Resources, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Girgis, Simone AU - Girgis S AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. FAU - Guo, Tiffany AU - Guo T AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. FAU - Brunetti, Luigi AU - Brunetti L AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. AD - Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. AD - Department of Pharmacy Practice and Administration, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. FAU - Kagan, Leonid AU - Kagan L AUID- ORCID: 0000-0003-3863-4757 AD - Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. lkagan@pharmacy.rutgers.edu. AD - Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. lkagan@pharmacy.rutgers.edu. LA - eng GR - R01GM124046/GM/NIGMS NIH HHS/United States GR - R01GM124046/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20230322 PL - United States TA - Pharm Res JT - Pharmaceutical research JID - 8406521 RN - 0 (Immunoglobulin G) SB - IM MH - Rats MH - Male MH - Humans MH - Animals MH - Infant MH - Rats, Zucker MH - *Obesity/drug therapy/metabolism MH - *Immunoglobulin G/therapeutic use MH - Body Weight PMC - PMC10033182 OTO - NOTNLM OT - antibodies OT - biologics OT - drug delivery OT - modeling and simulation OT - obesity COIS- Authors do not report any conflict of interest for this work. EDAT- 2023/03/24 06:00 MHDA- 2023/06/01 06:42 PMCR- 2023/03/22 CRDT- 2023/03/23 00:29 PHST- 2023/02/02 00:00 [received] PHST- 2023/03/01 00:00 [accepted] PHST- 2023/06/01 06:42 [medline] PHST- 2023/03/24 06:00 [pubmed] PHST- 2023/03/23 00:29 [entrez] PHST- 2023/03/22 00:00 [pmc-release] AID - 10.1007/s11095-023-03496-y [pii] AID - 3496 [pii] AID - 10.1007/s11095-023-03496-y [doi] PST - ppublish SO - Pharm Res. 2023 May;40(5):1223-1238. doi: 10.1007/s11095-023-03496-y. Epub 2023 Mar 22.