Tarjinder Sahota(1), Alienor Berges(1), Sharon Barton(2), Duncan Richards(3), Daren Austin(1), Stefano Zamuner(1)
(1) Clinical Pharmacology Modeling and Simulation, GSK, UK (2) Biopharm Statistics, GSK, UK (3) Academic DPU, GSK, UK
Introduction/Objectives: Amyloidosis is a rare fatal disease caused by progressive extracellular deposition of amyloid fibrils which damage tissue structure and function[1]. There are no treatments which directly target and clear amyloid from the tissues. A novel treatment approach is under development and targets serum amyloid P component (SAP), an endogeneous protein decorating amyloid fibrils in all forms of amyloidosis. Part of this approach involves the administration of a small palindromic molecule called Carboxy Pyrrolidine Hexanoyl Pyrrolidine Carboxylate (CPHPC) to deplete SAP to low concentrations in plasma. Free CPHPC has been found in preclinical studies to be cleared at almost glomerular filtration rate with a volume of distribution consistent with plasma and interstitial space distribution.
We propose the development of a mechanistic PK/PD model to allow for the prediction of CPHPC and SAP concentration-time profiles in plasma and in tissue. The model is being used to inform CPHPC dose selection in patients and will be subsequently extended to predict the effect of an additional antibody therapy[2].
Methods: Data came from an open label, adaptive study where CPHPC was administered to healthy volunteers and plasma CPHPC and SAP sampling were conducted from baseline (day 1) to follow up (day 28). All measurements were total concentrations (including free and bound fractions from the CPHPC-SAP complex).These data together with literature values of SAP turnover[3,4] were used to develop a mechanistic PKPD model using a non-linear mixed effect approach in NONMEM VII.
Results/Discussion: CPHPC disposition was best described by a two compartment model with rapid first order elimination (major elimination pathway) and target mediated clearance. Target mediated clearance was consistent with the assumption that the CPHPC-SAP complex was rapidly eliminated and the dissociation rate was negligible in comparison. SAP kinetics were best described by an indirect effect model with target mediated clearance, and a saturable peripheral compartment indicative of an extravascular binding to fixed non-amyloid ligands with negligible turnover and internalisation rates.
The model performed well in diagnostics and provided predictions of extravascular SAP concentration and plasma SAP concentration as a function of CPHPC exposure.
A potential limitation of the current approach is the availability of data in plasma only. Therefore, any difference in extravascular SAP concentrations between healthy volunteers and patients can only be inferred by the model.
References:
[1] Pepys, M.B. (2006) Amyloidosis. Annu. Rev. Med., 57: 223-241
[2] A. Berges PAGE 2012
[3] Hawkins, P.N (1990) J. Clin. Invest. 86: 1862-1869
[4] Jager P.L (1998) J Nucl Med. 39:699-706
Reference: PAGE 21 (2012) Abstr 2550 [www.page-meeting.org/?abstract=2550]
Poster: Other Drug/Disease Modelling