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Review
, 9 (2), 74-88

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

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Review

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

T Burt et al. Clin Transl Sci.

Abstract

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.

Figures

Figure 1
Figure 1
PKPD Continuum. phase 0/microdosing allows study of drug effects in the following domains: (I) – plasma PK; (II) – target PK; (III) – receptor binding and displacement; (IV) – pharmacological effects; biomarkers and/or clinical outcomes. PD, pharmacodynamics; PK, pharmacokinetics. Cu, concentration unbound in tissue; O, outcome; BM, biomarkers/metabolites; SEP, surrogate end points.
Figure 2
Figure 2
Conceptual representation of nonlinear drug disposition and extrapolation from microdose to therapeutic dose for (a) drugs showing linear PK and (b) drugs showing nonlinear (saturable) PK at therapeutic dose. Width of the blue and orange bars schematically represents ranges of substrate drug concentration after microdose and therapeutic dose, respectively. AUC, area under the concentration‐time curve; CL, clearance; Km, Michaelis‐Menten constant; [S], concentration of a substrate drug S.
Figure 3
Figure 3
eIND Strategic Timelines. Timelines are indicated on a scale of years before and after initiation of eIND clinical trial (vertical red line). In vitro and in vivo testing in support of full IND and phase I testing may continue in parallel to the phase 0 program so that no delays are incurred should a “go” decision be taken.

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