Sophie Gisbert, Guy Meno-Tetang, Herbert Struemper, Christine Barrett, Daren Austin
GSK Stockley Park, UK
Objectives: Renal clearance is typically not considered to be a major pathway of elimination of monoclonal antibody (mAb) due to their large molecular size [1]. However it becomes a major pathway of clearance of mAb in membranous nephropathy (MN) because of “leaky kidneys”. The purpose of this work is to show that urine and plasma PK may be used as early markers of clinical efficacy in MN as IgG-specific leakage in urine might be a more sensitive endpoint than non-specific proteinuria [2].
Methods: Historical Pharmacokinetics (PK) data of a typical IgG mAb were used to perform the following simulations for different multiple dosing regimen (every 4 weeks with or without a loading dose at week 2): (1) plasma PK of mAb in healthy and MN patients with different degrees of disease severity: renal clearance (CLR) equals to 0, 20, 40, 60, 80 and 100% of renal blood flow (2) amount excreted of mAb in urine for each disease severity and dosing regimen during the course of the treatment and for different urine collection intervals . Data from literature that described proteinuria as a function of glomerular filtration rate (GFR) were compared to the simulated amount of mAb excreted in urine.
Results: Simulation show that: (1) Involvement of kidneys in the elimination of the mAb leads to a proportional increase of its total clearance (2) Amount of mAb excreted in urine varies as a function of disease severity (3) Correlations were observed between both proteinuria and the amount of mAb excreted in urine and GFR.
Conclusions: Urine PK of mAb could be followed in MN patients to assess treatment effect.
References:
[1] Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharm Ther. 2008:84:548-558.
[2] Bazzi C, et al. Fractional Excretion of IgG Predicts Renal Outcome and Response to Therapy in Primary Focal Segmental Glomerulosclerosis: A Pilot Study. American Journal of Kidney Diseases, 2003:41:328-335
Reference: PAGE 22 (2013) Abstr 2807 [www.page-meeting.org/?abstract=2807]
Poster: Other Drug/Disease Modelling