FLOW CYTOMETRY IN PRECLINICAL TOXICOLOGY/SAFETY ASSESSMENT - Flow Cytometry in Drug Discovery and Development - page 119

FLOW CYTOMETRY IN PRECLINICAL
TOXICOLOGY/SAFETY ASSESSMENT

D AVID M C F ARLAND AND K RISTI R. H ARKINS

6.1 INTRODUCTION

6.1.1 Preclinical Toxicology

The primary departmental goal of preclinical toxicology (a.k.a. safety assessment) in
drug development is to identify and characterize drug-induced toxicity in test animals
by using appropriate animal models. This is accomplished through a large number
of individual studies, sometimes referred to as a “tox package,” designed to provide
specific data on the pharmacology/toxicology of the drug candidate including
determination of acute, subacute, and chronic toxicity, carcinogenicity, mutagenicity,
teratogenicity, and effects on the reproductive system. Various study designs are
employed. Dose ranging and/or dose escalating studies are typically completed early
in the safety assessment phase of drug development. This study design is meant to
provide maximum tolerated dose (MTD) and no observable (adverse) effect level
(NOEL or NOAEL), two important pieces of information that aid in selection of doses
for repeat dosing and/or chronic studies. Acute, single-dose experimental designs are
also used early in the safety phase to identify organs/tissues that are targets of toxicity.
After toxicity is identified, it is important to determine if the effect is reversible given
that the animal is allowed to recover for a period of time after administration of the
last dose. Reversibility studies may be done separately or a recovery group may be
included in a particular study design. It is possible to use varying routes of admin-
istration across studies, but it is critical to sufficiently investigate the route intended