Pharmacokinetics

Attrition of drug candidates over the course of drug discovery process if the biggest threat plaguing the biopharmaceutical industry. Pharmacokinetics  When he timelines gets prolonged and the costs shoot-up, due to the attrition, public health gets affected. The problem often results in the concerns about the public health and safety if the costs and timelines of drug discovery are extended. An early termination of a drug development program that will fail will help pharmaceutical companies in reducing the overall cost of R and D. An understanding of the reasons that contributed to the drug development failures is important for determining which drug candidate will fail. A significant cause of attrition is due to safety issues arising as a result of animal toxicity testing. Pharmacokinetic profile of the compound is important factor in the assessment of the safety of these compounds. Pharmacokinetic studies have become the most important factor in determining the success of the drug due to its impact on the cost and ability to predict the drug properties with great levels of accuracy.

Pharmacokinetics has evolved over the past two decades to become an integral part of the drug development process  especially in identifying a drug’s biological properties. Pharmacokinetics (PK) is dedicated to determining the mechanisms of a drug’s absorption, biodistribution, when it eliminated from the body and what it becomes. It is a study of how an organism affects a drug. These four processes together are called as ADME. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. The undesired PK characteristics include low bioavailability due to high extraction or poor absorption characteristics, short elimination half-life leading to short duration of action and excessive variability due to genetic or environmental factors. Many tools have been developed for predicting drug absorption, drug clearance and drug-drug interaction. Along with this PK parameters from animals to man have also been introduced. Hence, In vivo pharmacokinetic (PK) screening can be instrumental in the selection of lead compounds with desirable bioavailability profiles for further investigation in drug development programs.

There has been a rise in consideration of suitability of the PK profile of the drug candidate. This has led to the decrease in the early termination of the programs due to pharmacokinetic failings. This in turn has highlighted the other causes for compounds being considered unsuitable for drug development. Such reasons include inadequate safety and efficacy. These aspects can be addressed by understanding the complete pharmacokinetic behaviour along with pharmacodynamics profile of the drug candidate. Preclinical PD studies and the safety and efficacy biomarkers provide depth of data and help in assessment of safety of the drug candidates.

Detailing the relationship between the PK and PD is a critical factor for the development of new drugs. Additionally, PK/PD modeling can help increase the translation of in vitro compound potency to the in vivo setting, reduce the number of in vivo animal studies, and improve translation of findings from preclinical species into the clinical setting. The studies are designed with the basic assumptions of understanding relationship between the exposure of the medication and associated therapeutic activity. Such relationships are generally complex. So, we have to develop a dynamic preclinical studies model that will provide information to build a mathematical and mechanistically relevant PK/PD models. A data becomes more available, the initial models can be refined further. The ultimate output is a powerful predictive tool based on an in-depth understanding of the requirements for efficacy.

Well planned PK/PD study offers a rational approach to the efficient and informative drug development. This will help the teams in understanding the mechanism of action of a drug. Thus helping us to select the most optimal drug. Allocation of PK/PD modelling in the development programs ca help in minimization of in vivo models in the later phase and predict the dosage ranges for early clinical testing. PK/PD models allow integration of data from different studies in a logical manner based on the understanding of drug and disease. As the result of the above said reasons, PK and PD are becoming more and more important in the drug R and D.