Ta1_01

Changing the current drug development paradigm by unlocking the power of accelerator mass spectrometry

Lozac'h F¹, De Maria D², Fahrni S³, Marvalin C¹, Walles M¹, Camenisch G¹, Wacker L², Synal H²

¹Novartis Pharma AG, Basel, Switzerland, ²ETH Zurich, Zurich, Switzerland, ³Ionplus AG, Dietikon, Switzerland

Human metabolism ADME studies are pivotal in the clinical development of a pharmaceutical compound and usually mandatory to support acceptance by regulatory authorities. Conventionally, a radioactive therapeutic dose of ¹⁴C (manufactured according to GMP) is administered to healthy subjects or patients. However, to enable dosing of radioactivity to humans, dosimetry assessments need to be conducted by performing ADME studies in animals to determine and extrapolate relevant organ exposures to humans. Thus, due to high costs of these assessments and the attrition rate in early development, the human ADME study is usually conducted in a later phase.

Our idea is to change this current paradigm to a human first and human only paradigm, thanks to a microtracer approach in which trace amounts of radioactivity (ca. 1/1000 of conventional dose for ¹⁴C) can be dosed. The sensitivity of accelerator mass spectrometry (AMS) allows detecting these trace amounts of ¹⁴C. However, previous AMS instruments were big, expensive and run only with low throughput, which hampered a cost effective implementation for the profiling of biomedical samples.

Over the past 6 years, we have collaborated with ETH Zurich and the spin-off company Ionplus to miniaturize this AMS technology and increase both samples throughput and level of automation. Finally, we will internalize an instrument by end of 2022 to try to push and frontload human ADME studies earlier in the drug development process. Moreover, we hope that the availability of this technology will trigger discussions about sophisticated clinical and preclinical study designs using microtracer studies.