AMS CLINICAL STUDIES
Early clinical development is mainly focused on addressing safety, tolerability and pharmacology of a new chemical entity. Traditionally, incorporation of a radiolabeled component to the study enables detailed assessment of mass balance and metabolite profiling without the need to know chemical structures of all analytes being quantified. The design and conduct of these studies can significantly benefit by using AMS as the detection modality rather that liquid scintillation. Furthermore, radiolabeled IV dosing coupled with concomitant dosing of the non-labeled dose offers significant benefits in absolute bioavailability studies.
Common AMS Study Designs
Chemical vs. Radiochemical Dose
AMS clinical studies can be categorized based on the amount of radiochemical and chemical dose administered to each subject. From a radiochemical perspective, either a traditional amount of radioisotope is administered to each subject (typically greater than 10 μCi) or less than 250 nCi is administered in ‘lightly-labeled’ studies.
From a chemical perspective, the size of the administered chemical dose is primarily driven by the development stage for the drug candidate. Post-IND studies administer up to the expected pharmacologic dose while pre-IND studies may administer up to 100 μg or 1% of the expected pharmacologic dose to the human subject using an exploratory IND (Exp-IND). Post-IND absolute bioavailability studies are somewhat of a hybrid, where typically a 100 μg chemical dose and 100 nCi radiochemical dose are administered intravenously.
Benefits of Limiting Chemical Dose
There are two primary applications where reduction of chemical dose is advantages:
- Absoute Bioavailability Studies - These studies require the preparation of an IV formulation suitable for human administration. This presents a significant challenge in cases where a drug product has poor solubility at pharmacologic concentrations. This can be overcome with the preparation of drug product at subpharmacologic concentrations, such as 100 ug or less. By 14C-labeling the IV formulation, the IV dose can be distinguished isotopically from the unlabeled oral dose. This permits near simultaneous dosing of the unlabeled oral drug with the 14C-labeled IV drug. The subpharmacologic IV dose essentially eliminates any kinetic interference with the oral dose due to its reduced size. Standard LC-MS/MS methods are used to generate the oral area under the curve (AUC) while AMS methods are used to generate the IV AUC.
- Exploratory IND (Phase 0 Microdosing Studies) - Regulatory authorities have provided guidance on the design and conduct of microdosing studies. The significant difference in these studies is the limited safety studies and the reduced requirement of GMP material. Note that not all AMS studies are ‘microdosing’ studies, a term often mistakenly associated with all AMS studies. In fact, Accium has not conducted a single Phase 0 microdosing study. This is primarily due to slow industry adoption and acceptance of the approach and the limited benefits it offers relative to the time and costs associated with the technique, especially for large pharmaceutical companies. There may be a strategic benefit for smaller companies where Phase 0 microdosing can help to select a lead candidate from a series of candidates that are hard to prioritize using other approaches. In that regard, Phase 0 microdosing helps to reduce stage-specific risk but is does not reduce the cost and time overall development. For this reason, Accium does not actively propose the conduct of Phase 0 microdosing studies.
Benefits of Limiting Radiochemical Dose
Lightly labeled studies provide practical, ethical and design advantages over traditional radiolabeled studies. Dosing radiolabeled compounds to human subjects requires ethical considerations above and beyond standard safety concerns. Traditional methods that administer microCurie doses require dosimetry assessment in animals to ensure the radioisotope is eliminated from the subject and does not accumulate in sensitive organs. Administering nanoCurie doses eliminates dosimetry assessment in animals in most cases.
From a practical point of view, lightly labeled studies reduce the need to synthesize radiolabeled compounds with highly specific activities. Often, an initial synthesis batch with minimal 14C incorporation is more than sufficient to conduct a lightly labeled study. This reduces the overall cost and time required to produce a batch of material.
In other cases, certain chemical structures may undergo radiolysis and degradation, due to the high specific activity of the molecule. This problem is alleviated entirely with lightly labeled strategies.
Finally, sample handling, shipment to various laboratories and final disposition are greatly simplified when dosing lightly labeled compounds. It is rare to generate a sample that is categorized as radioactive material when less than approximately 250 nCi is administered to human subjects. Lightly labeled studies have other practical advantage when it comes to sample preparation and processing. Many of the laboratory steps, such as extraction and HPLC fractionation, can be performed in a laboratory that is not licensed to handle radioactive material. In fact, it is advantageous to perform this work in such a laboratory to reduce the likelihood of laboratory-to-sample cross-contamination.
Note that two study designs can often be combined into a single study, for example:
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Absolute Bioavailability – Concomitant administration of 14C-labeled IV dose and non-labeled oral dose to obtain absolute bioavailability of the oral dose (or other routes of administration).
Metabolite Profiling – Administration of a pharmacologic dose of a 14C-labeled compound to investigate the presence and quantity of unique human metabolites in support of the MIST Guidance.
Mass Balance – Lightly-labeled administration of a 14C-compound to investigate the mass balance, routes of elimination.
