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By Marijn Vlaming

Marijn VlamingMicrodosing is a method that can be used to safely assess the pharmacokinetics of candidate drugs directly in humans. With microdosing, extremely low doses of compounds that do not have any pharmacodynamic or toxicological effects can be administered to healthy volunteers. In the 2006 FDA guidance on exploratory investigational new drug studies, a microdose was defined as a dose less than 1/100th of the therapeutically active dose, ≤100 microgram or ≤30 nanomoles (for proteins). Detection of such low amounts of 14C-labeled drugs in biological matrices (e.g., plasma) is possible using the highly sensitive analytical technique accelerator mass spectrometry (AMS). Because a microdosing study is allowed after limited preclinical testing, it can significantly speed up timelines and reduce costs of drug development by collecting clinical data early in the drug development process.

Until now, AMS microdosing studies had been performed only with small molecule drugs and not with biotherapeutics. This was not previously attempted because this approach requires the administered drug to behave dose-linearly between the microdose and the therapeutic dose, which is true for most intravenously administered small molecule drugs. But not all protein therapeutics are expected to behave dose-linearly, and it was unknown whether this approach would be relevant for biotech products as well. In addition, for a microdosing study with AMS, the drug should be radiolabeled, and it was yet unclear which preclinical data were needed for the therapeutic protein and its 14C-labeled counterpart to obtain approval for a clinical microdosing study with a biopharmaceutical. Another issue was that 14C-labeling may affect the pharmacokinetics of a protein. These uncertainties appear to have prevented biopharmaceutical industry from performing microdosing studies for development of biotherapeutics.

To address these issues, our Dutch consortium consisting of TNO, Alloksys Life Sciences B.V., the Centre for Human Drug Research, and VUmc performed a clinical trial using the human recombinant protein rescuing alkaline phosphatase (hRESCAP) as a model compound. After discussion with the Dutch Medical Ethical Board, we developed a strategy for GMP-compliant 14C-labeling and subsequent preclinical investigation of hRESCAP. We administered a microdose (0.5 nmol, 53 μg) of the 14C-labeled protein to healthy volunteers. The results showed the pharmacokinetics that we expected for hRESCAP, and we could immediately proceed with administration of the protein at increasing dose levels, up to a therapeutically relevant dose. Interestingly, a clear dose-linearity in the pharmacokinetics was observed over the entire dose range; thus the microdose was predictive for therapeutic doses of hRESCAP.

Our results suggest that, at least for specific types of biotherapeutics, microdosing is a promising approach to obtain early clinical data. Using a microdose as a safe starting dose for first-in-human studies can significantly reduce costs, improve timelines, and reduce the number of laboratory animals needed for the development of biotechnology products. The next challenge in this field will be to investigate whether microdosing approaches can be applied to study efficacy of biotherapeutics, for example by using radiolabeled compounds as sensitive biomarkers for biological processes in humans.

To learn more about this research, view the abstract, no. W3073, through the 2014 AAPS National Biotechnology Conference NBC app online or via your mobile device, or visit her poster presentation on-site Wednesday, May 21, from 10:00 am to 2:00 pm PDT.

Marijn Vlaming is a biomedical engineer by training, and she obtained her Ph.D. in pharmacokinetics.  She works as a research scientist at TNO in Zeist, The Netherlands, where she leads preclinical and clinical pharmacokinetics studies in collaboration with academia and pharmaceutical companies.