Saskia Fuhrmann (1,4), Charlotte Kloft (3) and Wilhelm Huisinga (2)
(1) Institute of Biochemistry, Universitaet Potsdam, Germany; (2) Institute of Mathematics, Universitaet Potsdam, Germany; (3) Institute of Pharmacy, Dept. Clinical Pharmacy & Biochemistry, Freie Universitaet Berlin; (4) Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease Modelling, Freie Universitaet Berlin and Universitaet Potsdam, Germany
Objectives: Wild-type mice and xenograft mice are frequently used to study the PK and PD of monoclonal antibodies (mAbs). Protection from elimination by binding to the FcRn receptor is known to be a major process influencing the kinetics of mAbs as well as endogenous IgG (IgGendo). Since the therapeutic mAb concentrations following clinically relevant doses are typically manifold below the IgGendo concentrations [1], the clearance of mAb by this pathway appears to be linear. The levels of IgGendo in xenograft mice, however, are reduced, and this effect on mAb disposition has not yet been studied. The objective was to investigate the impact of FcRn expression and IgGendo level on mAb PK in the context of the simplified PBPK model [1] within two different scenarios, i.e. (i) FcRn wild-type (WT) mice following intravenous immunoglobulin (IVIG) therapy and (ii) immunodeficient i.e. SCID mice.
Methods: Physiological parameters were taken from [2]. The experimental plasma and tissue data of mAb (7E3), administered intravenously at 8 mg/kg following 3 different doses of IVIG, were extracted from [3] for FcRn WT mice. For SCID mice, the experimental plasma and tissue data of mAb (8C2), administered at 1 mg/kg and 25 mg/kg, were extracted from [4]. The steady-state plasma concentration of IgGendo was reported for FcRn wild-type mice [5] and for SCID mice [6]. The extraction ratios and FcRn expression levels were estimated for two groups of tissues (tight and leaky), based on tissue properties. We assumed no FcRn expression in plasma. MATLAB R2013a was used for modelling and simulations.
Results: The extended PBPK model accurately characterized the impact of IVIG on 7E3 PK, based on competition between IgG for binding to the FcRn receptor. Interestingly, we observed higher extraction ratios for tight tissues than in the leaky tissues. The estimated FcRn expression levels for WT mice would result in lower fraction unbound of mAb to FcRn and faster elimination kinetics in SCID mice, than observed experimentally. This suggests that also the FcRn expression levels are lower in immunodeficient mice compared to wild-type mice.
Conclusions: The concentration of total IgG and the elimination from tight tissues have a relevant impact on the PK of mAbs. This is important when investigating the influence of xenograft host models on tumour disposition.
References:
[1] L. Fronton et al. J Pharmacokinet Pharmacodyn, 41: 87-107, 2014.
[2] Brown et al. Toxicol Ind Health, 13:407, 1997.
[3] A.Garg. PhD thesis, State University of New York at Buffalo, July 2007.
[4] Abuqayyas. PhD thesis, State University of New York at Buffalo, May 2012.
[5] R.J.Hansen. PhD thesis, State University of New York at Buffalo, May 2002.
[6] R Deng et al. mAbs, 4: 101-109, 2012.
Reference: PAGE 24 (2015) Abstr 3613 [www.page-meeting.org/?abstract=3613]
Poster: Drug/Disease modeling - Absorption & PBPK