Current status and future perspective on preclinical pharmacokinetic and pharmacodynamic (PK/PD) analysis: Survey in Japan pharmaceutical manufacturers association (JPMA).

Preclinical pharmacokinetic/pharmacodynamic (PK/PD) analysis is an efficient tool for the translational research and proof of mechanism/concept in animals. The questionnaire survey on the practice of preclinical PK/PD analysis was conducted in the member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). According to the survey, 60% of companies conducted preclinical PK/PD analysis and its impact for drug development was different between each of the companies. The frequently analyzed therapeutic areas of preclinical PK/PD analysis were neurology, inflammation and metabolic disease, and those are different from the therapeutic area (infectious disease and oncology) in which PK/PD analysis was considered as effective by the present survey. Many companies which have used preclinical PK/PD analysis for the translation to human PK/PD and for the prediction of dose/regimen had good communication with other research & development (R&D) departments (e.g. pharmacology/clinical pharmacology). The increase in resources for preclinical PK/PD analysis including education was highly demanded. As a future perspective, the closer collaboration between pharmacokinetics scientists, pharmacologists, toxicologists and clinical pharmacologists and the increase in resources including upskilling and the comprehension of preclinical PK/PD analysis by the project team are considered to lead to efficient contributions to improve the success ratio of drug discovery and development.

Perspectives on non-clinical safety evaluation of drug metabolites through the JSOT workshop.

The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.