Dale E. Johnson

Predicting human safety: screening and computational approaches.

Current preclinical safety evaluation programs use a combination of computational methods, mechanistic in vitro screening and - primarily - in vivo experimentation to predict human toxicity. The rapid transition of pharmaceutical R&D into electronic R&D (e-R&D) makes it imperative that predictive safety testing also develops into an information-rich, knowledge-based process in the near future. Accordingly, enhanced databases and computational tools are expected to change the way the pharmaceutical industry assesses drug toxicity during discovery and early development. Expert use of prediction tools should lead to lower failure rates in drug development and decrease the cost and time involved in successful drug approval.

Web resources for drug toxicity.

Information on drug toxicity is used primarily by three segments of the health care industry: the consumer or patient, healthcare practitioners, and research and development (R&D) scientists in the pharmaceutical industry. The major focus of both consumers and health care practitioners is the provision of suitable information for the safe use of drugs for both individuals and specific patient populations. Therefore, accurate information on potential side effects and drug-drug and food-drug interactions is critical. For pharmaceutical scientists, the use of toxicity information is more complex and has become an essential part of the R&D process. The high rate of failures in drug development has precipitated the utilization of all available resources to gather relevant information that may improve the process of drug development. The web is a growing source of information and services for the pharmaceutical industry. Web-based resources for non-clinical drug development include tools for virtual discovery such as silico ADME/Toxicity programs, access to information regarding in vitro and in vivo testing, new data management options, and the latest regulatory guidelines and industry news. These resources are reviewed from the perspective of a toxicologist.

Reproductive Toxicological Evaluation of Omadine MDS

Reproductive toxicology studies with Omadine MDS were conducted using rats and rabbits, and plasma levels of the metabolite, 2-methylsulfonylpyridine (2-MSP), were assayed. In phase I (treated males, untreated females) of the fertility study, the no-effect level, for oral dosing, was 3.0 mg/kg; 7.5 mg/kg caused a decrease in male weight gain. In phase II (treated females, untreated males), the no-effect oral dose level was 1.0 mg/kg. At 3.0 mg/kg, decreases were seen in maternal body weight gain, the fertility index, and in total implantations and viable embryos at the 13-day uterine examination. Severe maternal toxicity including impaired motor function of limbs, decrease in weight gain, and mortality occurred at 7.5 mg/kg. In the perinatal/postnatal study, the no-effect level was 3.0 mg/kg. At 7.5 mg/kg, mortality was high, with a majority of animals dying during mid lactation. In the rat teratology study, the high dosage level, 30 mg/kg, dermally administered on Gestation Days 6 through 15 caused slight maternal toxicity, whereas 10 mg/kg produced none. These dosage levels corresponded to peak plasma levels on Gestation Day 10 of 470 and 1950 ng/ml 2-MSP at the 10- and 30-mg/kg dosage levels, respectively. In the rabbit, 5 mg/kg topically applied on Gestation Days 6 through 18 produced slight maternal toxicity while 1.5 mg/kg produced no maternal effects. The plasma levels of 2-MSP peaked on Days 12 and 15 of gestation. At 1.5 mg/kg these levels were 155 and 148 ng/ml; at 5.0 mg/kg, levels were 513 and 573 ng/ml. There was no teratogenic response seen in either species.

Designing non-clinical safety evaluation programmes for interferons and interleukins: A personal view

1. Toxicity of interferons and interleukins is produced only in animal models that are pharmacologically responsive to the molecule. Studies in a pharmacologically active species have been able to predict most human toxicities. However, when design issues, such as early neutralisation of biological effects, limit the value of animal studies in responsive species, the use of homologous proteins in a species not sensitive to the recombinant human protein may allow prediction of toxic effects.