Why is DMPK strategic?
Because DMPK is much more than box ticking and collecting slabs of information as part of the regulatory approval process.
For small molecules, a full understanding of Drug Metabolism (DM) is essential.
DMPK can be make or break for the success or failure of a molecule.
The way a drug is metabolised (and transported) can impact virtually all of the crucial aspects of small molecule drug development: Efficacy, Pharmacokinetics, Toxicity, Drug-Drug Interactions:
The generation of DMPK data should always be viewed as strategic:
Don't waste resource on information that is not needed.
Generate the data required at the appropriate time to de-risk your lead and aid progression (stage-dependent data).
+ What data is needed early?
+ What data indicates the molecule should be reviewed/stopped?
+ What data indicates the lead is better than the back up?
+ What data is better obtained using a radiolabelled form of the drug?
DMPK should be applied strategically (namely at the correct phases of drug development), using the appropriate species [metabolically] for safety assessment and using the correct modern in vitro techniques.
Unfortunately, outside of DDI and MIST, where there has been instructive regulatory guidance issued over the last 15 years, specific regulatory guidance for other areas of DMPK, for example ADME has been more limited and so a good working knowledge of current regulator thinking and requirements is vital for DMPK strategies.
Correct study plan designs are essential - ratified by an expert review.
Some crucial issues to consider are:
ADME
+ What are the precise Regulatory requirements for DMPK studies?
+ When are animal ADME studies needed?
+ What are the appropriate rodent/non-rodent animal models to use?
+ Will distribution by QWBA (Quantitative Whole Body Autobiography) be needed?
+ How much radiolabelled (14C) compound are needed for ADME studies?
+ Where can the 14C drug be synthesised?
+ How long should the synthesis take? How much (mCi/MBq) will be needed?
+ How much should these activities cost?
DDI
+ When are in vitro DDI studies needed?
+ The in vitro DDI studies are quite complex - how are the results interpreted for Regulatory submission in support of clinical trial requirements?
+ Are the DDI recommendations the same in USA and Europe? (and Japan)
+ What about major human metabolites?
(Note - FDA issued new DDI guidance in January 2021 - a link to this can be found here)
IND/Phase I Enabling
+ What DMPK information is needed for CTA/IND and First Time In Human clinical studies?
+ What other information is required?
+ Are in vitro DDI studies needed?
+ Is there regulatory guidance for IND/Phase I enabling?
+ How much should an IND enbling program cost? And how long should it take?
Safety Assessment
+ When should the FDA's MIST guidance (Metabolites In Safety Testing) be considered, which considers when safety data in animals can be extrapolated to humans?
+ When does a human metabolite become important when considering MIST?
+ The human 14C AME study provides the definitive human metabolite profile - when should this be conducted?
+ For the MIST-pivotal human 14C-AME study, where can the 14C API be manufactured to GMP?
+ What is the potential impact if a human-'disproportionate' metabolite is detected following the human 14C AME study?