DMPK studies are indispensable throughout the drug development process. Statistics suggest that almost 40% of potential drugs fail due to sub-optimal DMPK parameters. Therefore, DMPK (Drug Metabolism and Pharmacokinetic) has taken a leading role in the drug discovery process.
A predictive profile of a chemical can give sufficient information about its pharmacokinetic and pharmacodynamic characteristics. Methods utilized for predictive screening include in silico and in vitro models. The use of in vivo studies and models can be added as necessary in choosing the NCE (New Chemical Entity).
Reducing attrition remains a key goal for DMPK profiles. A predictive understanding of the ADME (Absorption, Distribution, Metabolism, and Excretion) properties of a prospective drug significantly reduces the chances of failure. Sometimes, the acronym used is ADMET to include toxicity, which is studied through the toxicokinetic properties of the drug.
DMPK, ADME, and Optimization of Compounds
Apart from poor DMPK profile, drug failure is also attributed to factors like bioavailability, drug-drug interactions (DDI), presence of active metabolites, toxicity, etc. With DMPK studies included in the early stages, chemicals that may perform poorly can be weeded out early.
For example, a drug administered orally may have poor intestinal absorption and/or low clearance. This can lead to low or variable bioavailability. Other problems may include a chemical’s risk of being denatured by gastric acid, binding to food, or changing with the first-pass metabolism. A suitable ADME profile and DMPK study may be able to avoid these problems.
Design Make Test Analyze (DMTA) cycle mated with a good DMPK profile is an excellent engine of lead development. It also opens up the possibility of optimizing a chemical to reach more desirable and suitable properties.
A key benefit of DMPK profiles has been in optimizing drugs for human use. The balancing of properties related to bioavailability, distribution, clearance, and DDI, has helped increase efficacy. While this applies to most drugs, the method has been especially useful for oral therapies.
Making allowances of DMPK and ADME in the discovery process helps create the proof-of-concept. This allows further use of the drug in preclinical studies, including in vivo studies on animals. dmpk Studies are utilized during the screening of the prospective drug as well as through all stages of development.
Apart from efficacy, DMPK assays may also be used to predict the human pharmacokinetic properties of the drug. Several methods may be used, including allometric scaling and in vitro-in vivo extrapolation. Each of these methods has its advantages or disadvantages. Allometric scaling, for example, is best used for low clearance compounds.
Using various DMPK parameters matched with ADME data, pharmacokinetics, and toxicokinetics helps in understanding exposure and clinical dosage. A drug may not necessarily behave the same way in humans as it does in vitro or during in vivo preclinical studies. Accurate translation of DMPK data from preclinical study to human models is necessary before its use in human clinical trials.
Given the advances in technology and data processing, it is expected that in silico methods will increase in relevance. They are still widely employed in drug development and the trend will continue. Wave 0 virtual screens with sufficiently high predictive capabilities for DMPK properties can make substantial improvements to monetary and time investments.