Miro Eigenmann, Ken Wang and Ludivine Fronton
Roche Pharma Research and Early Development, Pharmaceutical Sciences Roche Innovation Centre Basel, Hoffmann-La Roche Ltd., Basel
Objectives: Tissue specific blood flows (Qtis) and lymph flows (Ltis) play a major role for tissue distribution of therapeutic antibodies and are key parameters in physiologically-based pharmacokinetic (PBPK) models (1). Ltis values are currently empirically fixed as percentage of Qtis (2 or 4% for visceral or non-visceral organs) (2-4). Based on a simplified PBPK model (5),we (i) characterize the impact of Ltis on pharmacokinetics of monoclonal antibodies (mAbs); (ii) propose a range of probable Ltis values to be used in PBPK models.
Methods: Changes on mAb PK profiles caused by Ltis alterations were investigated by a sensitivity analysis in MATLAB R2013b. The extend of PK alteration was determined (i) qualitatively by visual inspection of 3D plots of altered Ltis values, time and plasma and tissue mAb concentrations; (ii) quantitatively with a gradient based scoring system.
To define a probable range for Ltis values a log-likelihood profiling (LLP) was conducted in Monolix 4.3.3 based on the PBPK model. Ltis values were sequentially fixed and altered and log-likelihood values derived. A log-likelihood profile and 95% CI were generated for each Ltis. Derived and currently assumed Ltis values were compared.
Results: Lowering Ltis values results in shallower PK profiles of mAbs, with lower Cmax, increased Tmax and slower removal from tissues. Altering Ltis of less perfused and big tissues (e.g skin or muscle) has major impact on the overall PK of mAbs, whereas in well perfused and smaller tissues (e.g. kidney) it has very limited overall impact. Main impact always occurs in the tissues where Ltis is altered.
The LLP defines a probable Ltis value range for muscle, skin and lung. For other tissues, e.g. kidney or gut, only a lower limit of Ltis could be derived. Overall the LLP suggests lower Ltis values as currently assumed.
Conclusions: Ltis affect several aspects of mAb PK: lower Ltis lead to lower Cmax and increased Tmax. Influence on the tissue itself is high while the impact on other organs is dampened by the interconnecting plasma compartment. This is new insight in differences and unexplained variability in PK of mAbs for e.g. patients with altered lymph flow due to immobility or inflammation. The LLP approach provides probable lymph flow values, is however limited for some tissues due to lack of early time points in PK data. The defined range of Ltis values from the LLP approach does not support current assumptions and suggests lower Ltis values.
References:
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[2] Covell DG, Barbet J, Holton OD, Black CD, Parker RJ, Weinstein JN. Pharmacokinetics of monoclonal immunoglobulin G1, F(ab’)2, and Fab’ in mice. Cancer Res. 1986 Aug;46(8):3969-78.
[3] Garg A, Balthasar JP. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. [Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov’t]. 2007 Oct;34(5):687-709.
[4] Jones HM, Gardner IB, Watson KJ. Modelling and PBPK simulation in drug discovery. Aaps J. [Comparative Study]. 2009 Mar;11(1):155-66.
[5] Fronton L, Pilari S, Huisinga W. Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models. J Pharmacokinet Pharmacodyn. [Research Support, Non-U.S. Gov’t]. 2014 Apr;41(2):87-107.
Reference: PAGE 25 (2016) Abstr 5828 [www.page-meeting.org/?abstract=5828]
Poster: Drug/Disease modeling - Absorption & PBPK