Development of a mechanistic PK/PD model to guide dose selection of a combined treatment for systemic amyloidosis
Alienor Berges1, Tarjinder Sahota1, Sharon Barton2, Duncan Richards3, Daren Austin1, Stefano Zamuner1
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. The high (mg/mL) circulating concentrations of SAP, combined with a fast turnover, make administration of anti-SAP antibody alone a challenging prospect as binding to circulating SAP may limit antibody distribution to target tissues. Therefore, a two stage approach combining a small and large molecule is proposed. A small palindromic molecule called Carboxy Pyrrolidine Hexanoyl Pyrrolidine Carboxylate (CPHPC) will be administered first in order to deplete SAP in plasma. The anti-SAP antibody will then be administered (while CPHPC is continued) and is expected to partition rapidly to amyloid deposits within tissues and induce a macrophage giant cell reaction resulting in clearance of the amyloid in situ.
We propose a mechanistic PK/PD model aimed to simultaneously predict the time profile of CPHPC, anti-SAP antibody and SAP in plasma and in tissues. The integrated use of all these data will allow investigation of the optimal dosing regimen of the antibody in combination with CPHPC.
Methods: A compartmental model including target mediated disposition was used to represent the different sites of interest (plasma, non amyloid tissues and amyloid tissues). The information related to SAP came from literature [2,3] and internal clinical data. The drug effect of CPHPC alone on SAP in plasma was evaluated in-house and was quantitatively described by a PKPD model using a non-linear mixed effect approach in NONMEM VII [4]. The anti-SAP antibody has not yet been administered to man and therefore data were limited to in-vitro binding assays and pre-clinical PK studies in plasma. A series of hypothetical plasma and tissue profiles of antibody was simulated using Berkley Madonna 8.3.18.
Results/Discussion: Given the limited current information on the antibody, we tested the antibody effect in the PKPD model using different scenarios, primarily related to antibody elimination (in the presence and absence of target mediated processes), and to the rate and extent of antibody distribution in the tissues.
Further imaging, liver biopsy and clinical data may be used to update the PKPD model in terms of antibody distribution across targeted organs affected by amyloid (e.g. liver, heart, kidney) and in terms of antibody-SAP complex in-situ degradation.
References:
[1]. Pepys, M.B. (2006) Amyloidosis. Annu. Rev. Med., 57: 223-241
[2]. Hawkins, P.N (1990) J. Clin. Invest. 86: 1862-1869
[3]. Jager P.L (1998) J Nucl Med. 39:699-706
[4]. T Sahota, PAGE 2012