DMPK

The study of DMPK has changed from a descriptive to a much more predictive science [3]. This is driven by great progress in bioanalytics, development of in vitro assays and in silica modeling/simulation, and a much better basic understanding of the processes. Thus, and fortunately, ADME-related attrition has lowered from around 40% in 1990 to around 10% in 2005 [13]. 

Instead of using surrogate measures for oral absorption with a lipophilicity or permeability assay in vitro, oral absorption can also be estimated in silica by using 

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The molecular structure is at the basis of physicochemical, DMPK, as well as safety/toxicity properties, as outlined in Fig. 2.1. Measurement and prediction of... 

Fig. 2.1 Dependency of DMPK and safety/toxicity properties on structural and physicochemical properties.

The third step is to optimize the lead molecule through iterative chemical synthesis and biological testing, aiming to obtain molecules with the required potency (typically nanomolar), selectivity, bioavailability, and DMPK (drug metabolism and pharmacokinetics) properties. This step usually requires considerable time and resources usually the synthesis of hundreds of compounds is needed to deduce a robust SAR (structure-activity relationship). Such resources can be considerably reduced and the... 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

As stated in the Section 6.1, one of the principal purposes of carrying out DMPK studies during the discovery phase is to reduce the failure rate during development. For DMPK this logically means predicting the pharmacokinetics that will be observed and hence the dose that will be required in man when clinical studies are carried out. 

One of the major goals of computational chemistry in the field of drug metabolism and pharmacokinetics (DMPK) is the prediction of oral availability. Several computational approaches have been published to predict this important parameter, starting from the molecular structure [1-3]. However, when applied to real case studies, none of these provided totally convincing results and, correspondingly, there is a lack of any general strategy to address this problem. 

Compound related includes drug metabolism and pharmacokinetics (DMPK), safety (off-target toxicity) and selectivity, and formulation and synthesis (cost of goods)... 

An analysis of 10 pharmaceutical companies [3] showed that the principal reasons for candidate failure in the year 2000 were as follows (estimated percentages from Figure 3 of Ref. [3]) toxicity/clinical safety (19% or 12%), efficacy (24%), commercial/other (19% or 6%), cost of goods (8%), DMPK (8%), and formulation (4%) (see Figure 1, adapted from... 

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

Several higher throughput in vitro assays may be used to assess various DMPK properties of NCEs. One common parameter is that HPLC/MS/MS is the method of choice for the analytical step.11 17 26 These higher throughput assays include the Caco-2 assay, p450 enzyme inhibition assay, and in vitro stability assay. Each assay has different requirements and solutions and they will be described individually. 

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

Experimental Perspectives in DMPK Related High-Throughput... 

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