The primary task of DMPK during the discovery support phase is to project the plasma exposure of potential therapeutic agents in humans by conducting appropriate studies in preclinical species or with human and animal in vitro systems. The ultimate mission for the DMPK group is to: (1) eliminate drug attrition in clinical development due to exposure-based failures, (2) eliminate metabolism based toxicities, and (3) minimize the potential for drug-drug interactions. In 2002, a new discovery paradigm "Discovery Assays by Stage (DABS)" was initiated at Millennium Pharmaceuticals, Inc. The discovery process is divided into four stages: (1) High Throughput Screen (HTS), (2) Hit to Lead (HTL), (3) Lead Optimization (LO), and (4) Development Candidate (DC) selection. The main emphasis of the HTS stage, for both medicinal chemistry and pharmacology, is to identify pharmacophore series / chemical scaffolds (i.e. Hits). The involvement of DMPK at this stage is predictive ADME (i.e. pADME). Metabolism scientists use databases (i.e. in silico) or personal experience/knowledge (i.e. in cerebro) to identify structural alerts related to "hits" and to predict potential metabolic liabilities. In vitro evaluation of CYP inhibition and reactive metabolite formation can be carried out at this stage to confirm/address potential metabolic liabilities of chemical scaffolds. The official support of DMPK starts at the "Hit to Lead" stage where both in vivo PK and in vitro ADME screens commence. Experience has taught us that an effective way to improve the DMPK properties of drug molecules is working on drug potency/efficacy and DMPK properties in parallel at the HTL stage, after DMPK issues have been identified for the lead series. Figure 3 illustrates DMPK's deliverables at HTL and LO stages.
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