DMPK has become a tool to optimize ADME properties in drug designing and screening. However, there are many related questions that often boggle the mind of a drug developer.

Most importantly, there is a need to identify appropriate ADME tests required to conduct for preclinical studies. As a result, a few clarifications have become mandatory before initiating the ADME program

1. What should a representative IND package contain?
Typical IND enabling package includes additional/confirmatory efficacy studies, toxicology using one or two species and tissue-cross reactivity typically for antibodies.

More specifically, an IND package must contain:

• Supportive Animal efficacy studies and all Toxicological studies under GLP.
• Toxicological studies to identify safe starting dose for human trials as well as potential target organs and way to monitor the toxicities

The selection of animal species, doses and duration depends on product and its intended use. All IND-enabling work should involve regular review of guidelines and frequent discussion with FDA.

2. What is the role of GLP in ADME-Tox studies?
GLP (Good Laboratory Practices) refers to a set of quality systems that ensures uniformity, reproducibility and authenticity of study data [1]. While certain preclinical studies can be conducted under non-GLP conditions, the use of GLP systems for performing ADME-tox studies indicates that the data obtained is accurate and can be used as a basis for further risk-benefit assessments. 

3. What is the meaning of a good PK profile?
A PK profile, or a pharmacokinetics profile, is the complete assessment of the path and metabolic activity of the molecule as it passes through different organ systems, from ingestion/uptake to excretion [2].  An ideal drug target has the following properties:

• Good solubility profile i.e., optimum solubility in water and octanol. Low water solubility or high first pass metabolism may lead to poor bioavailability.
• Bioavailability should be high with a good half life (t1/2).   Inadequate duration of action due to high clearance and short half-life could be one of the reason for drug failure.
• A good dose v/s exposure and PK/PD correlation i.e. kinetics should be linear.
• To avoid unanticipated drug-drug interactions, elimination via different pathways involving more than one enzyme is very important.
• Low CYP inhibition and induction is very advantageous.
• Metabolites of the drug candidate are non-reactive.

However, it must be noted that for highly potent NCEs, PK data can be poor. Therefore, in vivo efficacy models should be used for better interpretation

4. What is the role of in vitro ADME studies in the preclinical drug development process?
In vitro studies are used in conjunction with in vivo studies as a screening technique for drug candidates. Typically, they are used to

• Eliminate weak drug candidates in the early stages of drug discovery and to focus on potential candidate.
• Provides necessary data for selecting pre-clinical candidates, appropriate dosage forms and formulations for early ADME.
• Guide future animal and clinical studies for the selection of dose levels and regimen of administrations.
• Obtain information about metabolism and enzymes involved in metabolism.

It is crucial to understand the implications of these four questions before tailoring an ADME-tox program for your drug candidate(s). Getting a successful IND designation needs careful planning and a strong understanding of science. Above all, it needs the support of people who can combine both these qualities. Only then can you get the most out of your drug discovery pipeline!

References:
1. http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm135220.htm
2. http://www.msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/overview-of-pharmacokinetics