ABSTRACT
The World Health Organization (WHO) Scienti•c Group has de•ned a drug as “any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the bene•t of the recipient” [160]. The drug discovery/development process covers a wide range of therapeutic areas and treatment regimens and is a risky, multifaceted, expensive undertaking. The goal
is to develop a new product with therapeutic bene•ts (ef•- cacy) and few side effects (toxicity) [4]. The drug discovery/ development process for a new chemical entity (NCE) starts at the chemist’s computer with in silico generation and testing of theoretical molecules, followed by synthesis of molecules of interest, and then testing through various in vitro and in vivo pharmacology and toxicology models, including pharmacologic pro•ling (the determination of pharmacologic effects other than the desired therapeutic effect,
General Overview of Drug Development ................................................................................................................................. 333 Relevance of Animal Models in Toxicologic Assessment ........................................................................................................ 339 Toxicokinetics ........................................................................................................................................................................... 340 Toxicology Guidelines .............................................................................................................................................................. 341
Drug Development Timelines .............................................................................................................................................. 341 Regulatory Guidelines for Toxicity Testing ......................................................................................................................... 342
Acute, Subchronic, and Chronic Testing ......................................................................................................................... 342 Additional Toxicology Studies to Support Clinical Trials .............................................................................................. 344 Reproductive and Developmental Toxicity Studies ......................................................................................................... 344 Carcinogenicity Studies ................................................................................................................................................... 345
Chemical Entities ...................................................................................................................................................................... 347 Speci•c Agents ..................................................................................................................................................................... 349
Omeprazole (Prilosec®) ................................................................................................................................................... 349 Zidovudine (Retrovir®/AZT) ........................................................................................................................................... 352
Biological Entities ..................................................................................................................................................................... 354 Speci•c Agents ..................................................................................................................................................................... 354
Gonadotropin-Releasing Hormone Analogs ................................................................................................................... 355 Interferon ......................................................................................................................................................................... 355 Insulin .............................................................................................................................................................................. 356
Special Issues ............................................................................................................................................................................ 357 No-Observed-Adverse-Effect Level ..................................................................................................................................... 357 Immunotoxicology ............................................................................................................................................................... 357 Genetic Toxicology .............................................................................................................................................................. 360 Safety Pharmacology ........................................................................................................................................................... 361 Measure of Exposure............................................................................................................................................................ 362 Clinical Trials in Pediatric Populations ................................................................................................................................ 362 Nonclinical Evaluation of Anticancer Drugs ....................................................................................................................... 363 Alternative Methods for Carcinogenicity Determination ..................................................................................................... 364
Conclusion ................................................................................................................................................................................ 365 Questions ................................................................................................................................................................................... 366 Acknowledgment ...................................................................................................................................................................... 366 References ................................................................................................................................................................................. 366
ical plan for the •rst human dose (FHD).
