2001
   Basel, Switzerland

Dose-Concentration-FACS models for the monoclonal antibody ATM-027, developed for the treatment of Multiple Sclerosis (MS)

Zingmark, Per-Henrik* Edenius, Charlotte* and Karlsson Mats O**

*Experimental Medicine, AstraZeneca R&D, SE-151 85 Södertälje, Sweden **Division of Pharmacokinetics and Drug Therapy, Faculty of Pharmacy, Uppsala University, Box 591 SE-751 24 Uppsala, Sweden

Autoreactive T-cells are implicated in the pathogenesis of several autoimmune conditions e.g. rheumatoid arthritis, psoriasis and multiple sclerosis. A humanized antibody specific for a subgroup of T-cells thought to be associated with MS, was produced with the aim of developing an effective first line treatment for this disease. Flow cytometry was used to measure the effect of the antibody on the target T cells. Having access to such an easily monitored biomarker for pharmacological effect made it possible to collect several different variables suitable for PK/PD-modelling.

Two clinical studies on MS-patients have been conducted and in both trials plenty of PD-data was collected. These PD-variables include: number of the target T cells, the receptor expression of the target receptor on the T cells, both number of enhancing lesions and total volume of lesions as measured by MRI (Magnetic Resonance Imaging), Adverse Events and EDSS-score, i.e. scores on a scale measuring the disease state.

From the second clinical trial, data for these PD-variables were also available for patients on placebo treatment and the building of a disease model for multiple sclerosis with respect to all available PD-variables was planned.

The PK/PD relationship between ATM-027 concentrations and the effect on the target receptor expression on the T-cells, is the only relationship that has been modelled so far. This PD-response was initially categorised by the analyst to be trichotomous: dim, intermediate or bright, but later dichotomised to be high or low. This modelling is an example of PK/PD-modelling with ordered categorical PD data, as described by LB Sheiner (1). However, the underlying flow cytometry results that were categorised, were also available as a continuous variable and were later modelled using a traditional Emax model.

The modelling opportunities for this project and the results from the categorical vs continuous PK/PD modelling will be presented.

Reference: 1. Sheiner LB. A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data. Clin Pharmacol Ther 1994 Sep;56(3):309-22