Open AccessTarget Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis
Author(s) -
Sahota T,
Berges A,
Barton S,
Cookson L,
Zamuner S,
Richards D
Publication year - 2015
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.15
Subject(s) - amyloidosis , serum amyloid p component , amyloid (mycology) , medicine , antibody , serum amyloid a , drug , dosing , serum amyloid a protein , pharmacology , immunology , immunotherapy , pharmacokinetics , pathology , immune system , inflammation , c reactive protein
The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)‐1‐[6‐[(R)‐2‐carboxy‐pyrrolidin‐1‐yl]‐6‐oxo‐hexanoyl]pyrrolidine‐2‐carboxylic acid (CPHPC, GSK2315698, Ro 63‐8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti‐SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure‐response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first‐in‐human study with anti‐SAP antibodies. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 116–126; doi: 10.1002/psp4.15 ; published online on 4 February 2015.