Translational population target binding model for the anti-FcRn fragment antibody efgartigimod.

Publisher: Springer Country of Publication: United States NLM ID: 101096520 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-8744 (Electronic) Linking ISSN: 1567567X NLM ISO Abbreviation: J Pharmacokinet Pharmacodyn Subsets: MEDLINE

Publication: New York : Springer
Original Publication: Bristol, England ; New York, N.Y. : Kluwer Academic/Plenum Publishers, c2001-

Receptors, Fc*/metabolism ; Macaca fascicularis* ; Histocompatibility Antigens Class I*/metabolism ; Histocompatibility Antigens Class I*/immunology ; Immunoglobulin G*/metabolism; Animals ; Humans ; Rats ; Rabbits ; Mice ; Models, Biological ; Male ; Female ; Healthy Volunteers ; Protein Binding ; Species Specificity

Efgartigimod is a human IgG1 antibody Fc-fragment that lowers IgG levels through blockade of the neonatal Fc receptor (FcRn) and is being evaluated for the treatment of patients with severe autoimmune diseases mediated by pathogenic IgG autoantibodies. Engineered for increased FcRn affinity at both acidic and physiological pH, efgartigimod can outcompete endogenous IgG binding, preventing FcRn-mediated recycling of IgGs and resulting in increased lysosomal degradation. A population pharmacokinetic-pharmacodynamic (PKPD) model including FcRn binding was developed based on data from two healthy volunteer studies after single and repeated administration of efgartigimod. This model was able to simultaneously describe the serum efgartigimod and total IgG profiles across dose groups, using drug-induced FcRn receptor occupancy as driver of total IgG suppression. The model was expanded to describe the PKPD of efgartigimod in cynomolgus monkeys, rabbits, rats and mice. Most species differences were explainable by including the species-specific in vitro affinity for FcRn binding at pH 7.4 and by allometric scaling of the physiological parameters. In vitro-in vivo scaling proved crucial for translation success: the drug effect was over/underpredicted in rabbits/mice when ignoring the lower/higher binding affinity of efgartigimod for these species versus human, respectively. Given the successful model prediction of the PK and total IgG dynamics across species, it was concluded that the PKPD of efgartigimod can be characterized by target binding. From the model, it is suggested that the initial fast decrease of measurable unbound efgartigimod following dosing is the result of combined clearance of free drug and high affinity target binding, while the relatively slow terminal PK phase reflects release of bound drug from the receptor. High affinity target binding protects the drug from elimination and results in a sustained PD effect characterized by an increase in the IgG degradation rate constant with increasing target receptor occupancy.
Competing Interests: Declarations. Competing interests: Sven Hoefman and Tamara van Steeg are consultants at LAP&P. Judith Baumeister and Stefaan Rossenu are employees of argenx. Ingrid Ottevaere was an employee of argenx at the time of the study. This study was supported by argenx.
(© 2024. The Author(s).)

J Pharmacokinet Pharmacodyn. 2012 Feb;39(1):67-86. (PMID: 22143261)
Nature. 1989 Jan 12;337(6203):184-7. (PMID: 2911353)
Pharm Res. 1993 Jul;10(7):1093-5. (PMID: 8378254)
Int Immunol. 2003 Feb;15(2):187-95. (PMID: 12578848)
J Pharm Sci. 2019 Jan;108(1):701-713. (PMID: 30423340)
Clin Pharmacol Ther. 1994 Sep;56(3):248-52. (PMID: 7924119)
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5512-6. (PMID: 8643606)
CPT Pharmacometrics Syst Pharmacol. 2019 Oct;8(10):738-747. (PMID: 31464379)
J Immunol. 2007 Oct 1;179(7):4580-8. (PMID: 17878355)
J Biomed Biotechnol. 2012;2012:282989. (PMID: 22665983)
Pharm Res. 2005 Oct;22(10):1589-96. (PMID: 16180117)
CPT Pharmacometrics Syst Pharmacol. 2019 Aug;8(8):538-556. (PMID: 31044558)
Drugs. 2022 Feb;82(3):341-348. (PMID: 35179720)
CPT Pharmacometrics Syst Pharmacol. 2017 Feb;6(2):87-109. (PMID: 27884052)
Ther Deliv. 2011 Mar;2(3):359-68. (PMID: 22834006)
Nat Rev Immunol. 2007 Sep;7(9):715-25. (PMID: 17703228)
J Clin Invest. 1970 Apr;49(4):673-80. (PMID: 5443170)
Curr Drug Metab. 2009 Sep;10(7):661-91. (PMID: 19702530)
Drug Metab Pharmacokinet. 2009;24(4):318-32. (PMID: 19745559)
MAbs. 2014 May-Jun;6(3):689-96. (PMID: 24572100)
MAbs. 2018 Jul;10(5):751-764. (PMID: 29634430)
Autoimmunity. 2022 Dec;55(8):620-631. (PMID: 36036539)
J Clin Invest. 2018 Oct 1;128(10):4372-4386. (PMID: 30040076)
J Pharmacokinet Pharmacodyn. 2008 Oct;35(5):573-91. (PMID: 19005743)
Biomolecules. 2019 Aug 15;9(8):. (PMID: 31443181)
J Pharm Sci. 2019 Jan;108(1):714-724. (PMID: 30471293)
J Pharmacokinet Pharmacodyn. 2012 Oct;39(5):429-51. (PMID: 22851162)
J Histochem Cytochem. 2017 Jun;65(6):321-333. (PMID: 28402755)
Am J Physiol Renal Physiol. 2001 Oct;281(4):F579-96. (PMID: 11553505)
Circ Res. 1978 Sep;43(3):337-47. (PMID: 354819)
Front Immunol. 2015 Jan 26;5:682. (PMID: 25674083)
Expert Rev Clin Immunol. 2022 Dec;18(12):1207-1215. (PMID: 36227228)
J Pharm Sci. 2004 Nov;93(11):2645-68. (PMID: 15389672)

Keywords: Efgartigimod; FcRn; Interspecies translation; Population PKPD modelling

0 (Receptors, Fc)
0 (Histocompatibility Antigens Class I)
TW3XAW0RCY (Fc receptor, neonatal)
0 (Immunoglobulin G)

Date Created: 20241205 Date Completed: 20241205 Latest Revision: 20241208

20241209

PMC11621151

10.1007/s10928-024-09952-5

39636455