Timing of carcinogenicity studies and predictability of genotoxicity for tumorigenicity in anti-HIV drug development.

The timing of carcinogenicity studies in parallel with the clinical development of anti-human immunodeficiency virus (HIV) drugs has been flexible for most cases in the past. This includes postponement of the initiation of the studies and submission of final audited reports to the US Food and Drug Administration (FDA) for a new drug application (NDA) approval. We address this regulatory practice for anti-HIV drugs for which, in the past, there had been no effective treatment.

Green tea extract-induced lethal toxicity in fasted but not in nonfasted dogs.

Recent chronic toxicity studies performed on green tea extracts in fasted dogs have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Key findings included necrosis of hepatic cells, gastrointestinal epithelia and renal tubules, atrophy of reproductive organs, atrophy and necrosis of hematopoietic tissues, and associated hematological changes. The polyphenol cachetins (a mixture of primarily epigallocatechin gallate [≥55%]; plus up to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate) appeared to be the causative agents for the observed toxicities because they are the active ingredients of green tea extract studied.

A New Classification of Prodrugs: Regulatory Perspectives.

Many therapeutic agents are manufactured and administered in prodrug forms. In this paper, a new classification system for prodrugs is proposed to provide useful information about where in the body a prodrug is converted to the active drug. In this system, prodrugs are classified into Type I or Type II and the respective Subtypes IA, IB, IIA, IIB or IIC based on their sites of conversion into the final active drug form.

Current regulatory perspectives on genotoxicity testing for botanical drug product development in the U.S.A.

Genotoxicity testing is an important part of preclinical safety assessment of new drugs and is required prior to Phase I/II clinical trials. It is designed to detect genetic damage such as gene mutations and chromosomal aberration, which may be reflected in tumorigenic or heritable mutation potential of the drug. Botanical new drugs in the U.

Current regulatory toxicology perspectives on the development of herbal medicines to prescription drug products in the United States.

Toxicological studies constitute an essential part of the effort in developing an herbal medicine into a drug product. The US food and drug administration (FDA) published a guidance to assist academic and industry sponsors in the development of this unique group of drug products, and has recently approved an new drug application (NDA) based on green tea extract (Veregen) for topical treatment of genital and perianal warts. In this article, current regulatory views on issues related to requirements and recommendations on various types of nonclinical toxicity studies in support of clinical trials and filing an NDA for a herbal medicine, including pharm/tox aspects of green tea extract (Veregen) NDA, are discussed.

Regulatory perspectives of Type II prodrug development and time-dependent toxicity management: nonclinical Pharm/Tox analysis and the role of comparative toxicology.

Many therapeutic agents are prepared in prodrug forms, which are classified into Type I, II and subtypes A, B based on their sites of conversion. Recently, an increasing number of INDs have appeared as Type II prodrugs that often contain dual tracks of toxicity profile exploration, one on the prodrug and another on the active drug. A comparative toxicology analysis is introduced here to assist reviewers to evaluate the dual toxicity profiles effectively.

Preclinical development of new drugs that enhance thyroid hormone metabolism and clearance: inadequacy of using rats as an animal model for predicting human risks in an IND and NDA.

New drugs that enhance metabolism or clearance of thyroid hormones in rats often trigger a sequence of toxicity events during chronic administration: reduction of thyroxine, elevation of thyroid-stimulating hormone (TSH) levels, and thyroid gland hyperfunction/growth. Hepatocellular hypertrophy and thyroid follicular hyperplasia are often observed with increased liver and thyroid organ weights. This unique toxicity profile seems to be species-specific because the thyroxine in rodents is metabolized rapidly, without thyroid hormone-binding globulin that serves as a reserve, as in humans.