Toxicological support studies

Use data from preclinical pharmacology toxicology ( safety ) studies to support the safety of clinical trials. 

Toxicokinetics is defined as the generation of pharmacokinetic data, either as an integral component in the conduct of nonclinical toxicity studies or in specially designed supportive studies, in order to assess systemic exposure. These data may be used in the interpretation of toxicology findings and their relevance to clinical safety issues (ICH Guidance Toxicokinetics 1994). 

In addition to being used for screening purposes for new dmg development, labeled dmgs and ligands are widely used by pharmaceutical companies for metabohc, bioavailabihty, and toxicological studies to support new dmg appHcations for FDA approval. 

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. 

Male mice exposed to 7.3 mg/kg/day for 13 weeks had significantly decreased spleen weights and decreased neutrophil counts (Hoechst 1984b), indicating that immune activity in mice may also be affected. An intermediate-duration oral MRL of 0.005 mg/kg/day was derived based on the NOAEL of 0.45 mg/kg/day for immunotoxicity identified in the Banerjee and Hussain (1986) study. In support of these positive findings, Khurana et al. (1998) observed decreased macrophage functionality, in the absence of any other apparent toxicological effects, in 1-day-old broiler chicks fed 30 ppm endosulfan in the diet for 4 or 8 weeks. 

Reliable residue data are generated during the development of an a.i. to support the assessment of the consumer risk (residue data and toxicological data) and the impact on the environment (fate and behavior, efficacy and ecotoxicological data). It is critical that these analytical methods are reliably validated. In the guidance document SANCO/3029/99 rev. 4 (11/07/00), harmonized requirements for the residue analytical method are described. Validated analytical methods are required for the following studies ... 

Thompson, J. A. Carlson, T. J. Sun, Y. Dwyer-Nield, L. D. Malkinson, A. M. Studies using structural analogs and inbred strain differences to support a role for quinone methide metabolites of butylated hydroxytoluene (BHT) in mouse lung tumor promotion. Toxicology 2001, 160, 197-205. 

As such, an asymmetric synthesis of tarantabant had been demonstrated centered around a DKR as the key step to set both stereocenters in a single catalytic step. The synthesis proceeded in six steps and 40% yield from the ketone rac-13. This route was found to be robust and reliable and generated in excess of 70 kg of API in various campaigns from both preparative laboratories and pilot plant facilities, and provided support for the project through longer term toxicology and clinical studies [13]. 

---