Streamlining the Delivery of 14C Human ADME Data: An ADME Q&A Roundtable

Learn about techniques for streamlining human ADME studies from experts at Quotient Sciences and The Netherlands Organization for Applied Scientific Research (TNO).

Iain Shaw, Senior Director of 14C Enabled Drug Development at Quotient Sciences, and Wouter Vaes, microtracer expert at The Netherlands Organization for Applied Scientific Research (TNO), are joined by a panel of synthesis, regulatory and clinical pharmacology experts for a Q&A focused on streamlining human ADME studies.

Summary

For most drug programs, a key step for inclusion in a successful global regulatory filing is to conduct a human absorption, distribution, metabolism, and excretion (ADME) study. Regulatory agencies require ADME studies to describe the disposition of a drug after it has been dosed in human subjects providing data to explain the pharmacokinetics (PK), metabolism, and safety of the drug. Traditionally, these types of studies usually take place towards the end of Phase II development, as developers are gearing up for Phase III and beyond. However, recently there has been a clear shift occurring within the industry, moving these types of studies earlier in clinical development due to integrated delivery platforms and the use of accelerator mass spectrometry in this field.

At Quotient Sciences, our integrated Synthesis-to-Clinic® programs support human ADME studies from radiosynthesis to the final clinical study report, all under a single program manager and single contract. This approach allows for 14C drug substances to be efficiently synthesized to support non-clinical and clinical requirements. Integrated pharmaceutical sciences facilities provide formulation development, real-time Good Manufacturing Practice (GMP) manufacturing, and qualified person (QP) release of 14C drug products, which enable us to seamlessly supply formulations for ADME studies to healthy volunteers at our in-house clinic or to patients at specialist clinics.

In a typical microtracer study, the radioactive 14C drug dose is generally in the order of about 0.8-1 µCi, and thus a quantitative whole-body autoradiography (QWBA) is not required. Having human ADME data available as early as Phase I can be instrumental in making better and more informed decisions during further clinical development. Another advantage is that early human ADME data reduces the requirement to conduct radiolabelled ADME studies in animals. The 0.8-1 µCi radioactive dose is 100 times lower than in a classical mass balance study, and therefore such a low dose requires substantially better bioanalytical sensitivities than conventional liquid scintillation counting can provide.

Quotient Sciences works with TNO, the largest accelerator mass spectrometer (AMS) service provider worldwide, where there are three operational AMSs, all equipped with TNO’s unique rapid sample preparation technology, which reduces sample preparation time from several days to minutes. With this technology, TNO can provide pharmaceutical and biotech companies with all the analytical support that is required for a two-arm microtracer study design. TNO provides AMS services for mass balance and metabolite profiling, and is also equipped for all metabolite identification, using liquid chromatography with high-resolution tandem mass spectrometry (LC-hrMS/MS). For the absolute bioavailability (AB) arm of such a study, TNO provides robust data to derive the %AB, while also providing an estimate for the fraction absorbed.

Key discussion points:

• Challenges and considerations for developers when conducting a human ADME study
• Regulatory requirements for human ADME studies
• Utilizing a U-tracer study vs a classical human ADME study approach
• Key advantages in conducting microtracer AMS studies in early clinical development
• Benefits in using an integrated Synthesis-to-Clinic approach in delivering ADME studies