Pharmacokinetic-pharmacodynamic model to predict the pharmacological depletion of serum amyloid P component in healthy volunteers

Tarjinder Sahota, Alienor Berges, Sharon Barton, Eloisa Brook, Stefano Zamuner, Daren Austin. GlaxoSmithKline - Biopharm Clinical Pharmacology & Biometrics, Stockley Park - UB11 1BT, UK.

Amyloidosis is a rare fatal disease caused by progressive extracellular deposition of amyloid fibrils which damage tissue structure and function.1 Amyloid deposits always contain the normal, non-fibrillar plasma protein, serum amyloid P component (SAP), which contributes to amyloid formation and persistence. There are no treatments which directly target and clear amyloid from the tissues.

(R)-1-[6-[(R)-2-Carboxy-Pyrrolidin-1-yl]-6-oxo-Hexanoyl]Pyrrolidine-2-Carboxylic acid (CPHPC) is a palindromic bis(D-proline) compound which is avidly bound by circulating human SAP to form complexes in which two native pentameric SAP molecules are stably cross linked by 5 CPHPC molecules.2,3 This complex is very rapidly cleared from the circulation by the liver leading, despite the daily production of 50-100 mg of new SAP, to the almost complete depletion of SAP from the blood. GSK is working with Pentraxin Therapeutics Ltd on a potential therapy for systemic amyloidosis using monoclonal anti-human SAP antibodies, for the safe and effective administration of which, prior depletion of circulating SAP by CPHPC is essential.4

We have recently conducted an open label, adaptive design study with 21 subjects, to characterize the relationship between plasma exposure of CPHPC and plasma SAP depletion in healthy volunteers. The study included 6 different 1-hour IV dosing regimens and 8 different 24-hour IV dosing regimens. Rich PK and SAP sampling were conducted from baseline (day -1) to follow up (day 28). A population PK-PD model using a non-linear mixed effect approach was developed in NONMEM VII.

The CPHPC pharmacokinetic time course profile was adequately described by a two-compartment model, with rapid systemic clearance. No evidence of saturation in clearance was detected. Rapid and substantial SAP depletion was observed after 1 h IV infusion (∼90% at higher doses). Prolonged infusion (>4 h) produced further SAP depletion up to 24 h. An indirect response model provided the best description of the CPHPC-SAP exposure response relationship.5. The developed PK-PD model is aimed to be subsequently refined by the introduction of antibody binding kinetics as a means of predicting the effects of a subsequent antibody therapy in amyloidosis patients.

1. Pepys, M.B. (2006) Amyloidosis. Annu. Rev. Med., 57: 223-241.

2. Pepys, M.B. et al (2002) Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature, 417: 254-259.

3. Kolstoe, S.E. et al (2009) Molecular dissection of Alzheimer’s disease neuropathology by depletion of serum amyloid P component. Proc. Natl. Acad. Sci. USA, 106: 7619-7623.

4. Bodin, K. et al (2010) Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature, 468: 93-97.

5. Krzyzanski, W., Jusko, W.J. (1998) Mathematical formalism and characteristics of four basic models of indirect pharmacodynamic responses for drug infusions. J Pharmacokinet Biopharm. 26: 385-408.