Microdose Studies
Stakeholders in the drug development process generally agree that both the time and expense required to move a new chemical entity from drug discovery to approval are too great, and seek various solutions to expedite the process. One solution is the utilization of “microdose” studies. After several years of discussion, the FDA published guidance in January 2006 regarding use of microdose studies, including an exploratory IND (expIND) regulatory framework particularly suited to early compound selection.
One attractive feature of microdose studies is the ability to obtain human data early, at low risk to participants. A microdose is defined as “1/100th of the amount expected to have a pharmacological effect, up to 100 micrograms.” Doses in this range require very sensitive assays, which may exceed the limits of “wet lab” methods such as LC/MS/MS. However, with an isotope such as 14C and utilization of accelerator mass spectrometry (AMS), the threshold of detection is generally sensitive enough for useful data following administration of nanogram level doses of the study drug.
Medications for selected indications may require particular pharmacokinetic profiles for safety and efficacy, especially anti-infectives and certain CNS and cardiovascular products. Animal models may or may not accurately predict human pharmacokinetics, and approximately 25% of new chemical entities fail to reach or demonstrate proof of concept due to an undesirable PK profile. Microdose studies under an expIND have been successful in providing sufficient human PK data to allow decision making regarding compound selection and prioritizing further development, thus saving time and money compared with conventional tools, and the data may guide your First Time In Humans study design under a conventional IND.
In addition, AMS and microdose technology may be useful tools to answer questions beyond compound selection. Microdose studies may document penetration into crucial target tissue compartments of distribution. Also, when combined or compared with a larger “cold” dose, microdose technology may define absolute bioavailability to guide further formulation development. And, if a small labeled dose is combined with a conventional dose during an otherwise conventional Phase I study, AMS technology allows determination of mass balance and can indicate the presence or absence of unique human metabolites.
Dr. Ruckle has been an active participant in the dialogue regarding microdose studies since 2005, when he conducted his first 14C labeled microdose study. Pacific Pharma Group, LLC is prepared to help you weigh the pros and cons of utilizing microdose technology as part of your compound development strategy.
