[Frontiers in Bioscience E2, 266-278, January 1, 2010]

Application and review of the separate ray model to investigate interaction effects

Roel Straetemans1, Luc Bijnens1

1Johnson and Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica N.V., Beerse Belgium

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Statistical Methodologies
3.1. Concentration-response model
3.2. The Separate Ray Model
3.3. Changes to original published work
3.4. Hard- and software
4. Overview of Applications
4.1. First data set: Combination of trimetrexate and AG2034 with 2.3ÁM folic acid
4.2. Second data set: Combination of trimetrexate and AG2034 with 78ÁM folic acid
5. Summary and Perspective
6. Acknowledgement
7. References

1. ABSTRACT

In this paper we review the application of the Separate Ray Model to analyze drug combination experiments coming from a fixed ratio design. The idea is the joint fit of separate concentration response curves to each ray under investigation leading to an interaction index for each together with a 95 percent Confidence Interval. The approach is a simple and easy to implement parametric modeling approach and allows estimation and testing of drug interactions based on regularly sampling in the entire space of all combinations going from pure compound A to pure compound B. The analysis is implemented using the SAS/STAT procedure NLMIXED. Two datasets were provided for the modeling exercise. One included different qualitative effects with some rays showing synergy, others antagonism and again others additivity. The second dataset involved the presence of very large synergy together with different observed background effects for the individual rays. The Separate Ray Model is able to handle these practical issues making it a flexible tool to investigate drug interaction experiments using a fixed ratio design.