L. Banken, J.-L. Steimer, F. Hemmings, H. Wiltshire
F. Hoffmann-La Roche Ltd, Basel (CH) & Welwyn (UK)
Objectives A mathematical pharmacokinetic model was developed for the description and prediction of the time-course of total and unbound plasma concentration of Ro 32-3555, a cartilage protecting agent in clinical evaluation for therapy of rheumatoid arthritis. The goals were to assess the role of nonlinear protein binding of Ro 32-3555 to a1-acid glycoprotein (AGP) and its influence on the total and free concentration over time, and to predict exposure to unbound concentration at doses intended for clinical testing and therapeutic use.
Methods A combined analysis of four clinical pharmacology studies in healthy volunteers and one in rheumatoid arthritis patients was carried out with a total sample size 117 subjects. All studies included measurement of total concentration of Ro 32-3555, some also of unbound concentration in plasma (N=36) and of predose AGP (N=33).
Using the software NONMEM, a nonlinear mixed effects pharmacokinetic model has been developed to describe the time-course of plasma concentrations after single and multiple dosing. The relationship of protein-bound to unbound concentration was described through a nonlinear (hyperbolic) relationship. The basic PK model, a one compartment open model for unbound drug, was further refined in successive model-building steps, based on the diagnostics from the data fitting.
Results The pharmacokinetics of total & unbound Ro 32-3555 could be adequately described by a 2 compartment model with first order absorption and lag time, specific protein binding to AGP in the plasma (central compartment) and specific binding in the peripheral compartment (“the tissue”). Some variations in bioavailability and clearance between the studies could not be described by other covariables than “Study”. In the present pooled analysis with a limited number of covariables (such as age, race), no influential covariables on PK parameters have been found, except AGP concentration and Study.
The current “final” model has the following properties. 1)For exposure based on unbound concentration (AUCu and Cmaxu), no relevant changes occur with variation in AGP. This result largely reflects that Ro 32-3555 is a low-clearance drug, so that its clearance with respect to unbound drug (CLu) is little affected by changes in binding; 2)At a given dose, total concentration AUC and Cmax increase with increasing AGP concentration. 3) The interpretation of PK data based on total concentration may be misleading, especially in patients where AGP levels vary much within and between subjects; 4)The consistency between in vitro and in vivo binding parameters in the 2nd compartment suggests that it may be closely linked to the site of action.
Discussion and concluding remarks The integrated model-based analysis suggests that changes in binding of Ro 32-3555 due to variation in AGP do influence the exposure to total drug, but not to unbound drug. Under the premise that the driving force for effects is unbound drug, this result suggests that changes with time, with disease, and across subjects (as for race or gender) in the concentration of plasma AGP are not of special concern for therapy with Ro 32-3555. The interpretation of the Study effect remains unclear.
Reference: PAGE 10 (2001) Abstr 212 [www.page-meeting.org/?abstract=212]
Poster: poster