Successful drug development despite adverse preclinical findings part 2: examples

Abstract

To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions.

Keywords: adverse preclinical finding; carcinogenicity; genotoxicity; morphologic toxicity; reproductive toxicity; weight-of-evidence approach.

Fig. 1

Squamous cell metaplasia of the endometrium of a female OFA rat treated in feed for 53 weeks with 82 mg/kg bw/day of bromocriptine. H&E, lens 10×.

Fig. 2

Uterine adenocarcinomas of an OFA rat treated in feed for 100 weeks with 44.5 mg/kg bw/day of bromocriptine. H&E, lens 10× .

Fig. 3

Leydig cell hyperplasia (one focus in the center of the figure) and adenomas (one seen on the right side of the figure) of the testis of a Kfm:WIST rat treated in feed for 129 weeks with 1.7 mg/kg bw/day of mesulergine. H&E, lens 10×.

Fig. 4

Subacute arteritis/periarteritis in a SIV 50 rat renal artery with necrosis, inflammation, and proliferation of fibroblasts; undisclosed drug. H&E, lens 25× .

Fig. 5

Adenosis in the duodenum of a Wistar rat after a 26 week oral treatment with 100 mg/kg bw/day of a VEGF-receptor inhibitor. H&E, lens 10×.

Fig. 6

Phospholipidosis with foam cells in lungs of a SIV 50 rat following 16 daily oral doses of 40 mg/kg bw/day of chlorphentermine. H&E, lens 25×.

Fig. 7

Hypertrophic osteopathy in a female Wistar rat treated orally for 47 days with 130 mg/kg bw/day of the PDE IV inhibitor SDZ MNS 949. H&E, lens 10×