title: Experimental designs for detecting synergy and antagonism between two drugs in a pre-clinical study.
abstract: The identification of synergistic interactions between combinations of drugs is an important area within drug discovery and development. Pre-clinically, large numbers of screening studies to identify synergistic pairs of compounds can often be ran, necessitating efficient and robust experimental designs. We consider experimental designs for detecting interaction between two drugs in a pre-clinical in vitro assay in the presence of uncertainty of the monotherapy response. The monotherapies are assumed to follow the Hill equation with common lower and upper asymptotes, and a common variance. The optimality criterion used is the variance of the interaction parameter. We focus on ray designs and investigate two algorithms for selecting the optimum set of dose combinations. The first is a forward algorithm in which design points are added sequentially. This is found to give useful solutions in simple cases but can lack robustness when knowledge about the monotherapy parameters is insufficient. The second algorithm is a more pragmatic approach where the design points are constrained to be distributed log-normally along the rays and monotherapy doses. We find that the pragmatic algorithm is more stable than the forward algorithm, and even when the forward algorithm has converged, the pragmatic algorithm can still out-perform it. Practically, we find that good designs for detecting an interaction have equal numbers of points on monotherapies and combination therapies, with those points typically placed in positions where a 50% response is expected. More uncertainty in monotherapy parameters leads to an optimal design with design points that are more spread out.
authors: Health eResearch Centre, Farr Institute, University of Manchester, Manchester, UK.
authors: Matthew
authors: M
authors: Sperrin
authors: Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
authors: Helene
authors: H
authors: Thygesen
authors: School of Dentistry, University of Manchester, Manchester, UK.
authors: Ting-Li
authors: TL
authors: Su
authors: Discovery StatisticsAstraZeneca R&D, Alderley Park, Cheshire, UK.
authors: Chris
authors: C
authors: Harbron
authors: Medical and Pharmaceutical Statistics Research Unit, Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
authors: Anne
authors: A
authors: Whitehead
mesh_terms: D000465:Algorithms; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D015233:Models, Statistical; D012107:Research Design
keywords: Loewe additivity; drug combination; experimental design; interaction index; synergy