Table 4.
Current and emerging applications of phase 0 / microdosing approaches. “Current applications” refers to phase 0 clinical studies that were part of new drug development, or those used in multiple research settings to obtain information on existing drugs in new populations or circumstances. “Emerging applications” denotes new and theoretical applications that are in the early stages of development and/or validation
| Examples and references | |
|---|---|
| Current applications | |
| PK and BA | Study of drug disposition (e.g., absorption, distribution, metabolism, excretion, bioavailability [ADME], TMDD);19 effectiveness‐related PK (i.e., PK parameters that directly impact on safety and efficacy).20 |
| DDI | Cocktail and cassette DDI studies.21, 22 |
| PD/Localization/Proof of mechanism | Phosphorylation in PBMCs.16 DNA adducts in PBMCs.17 Target tissue localization.23, 24, 25 |
| Vulnerable populations | Pediatric studies of drug disposition.26, 27, 28, 29 Future applications may apply also to women (including pregnant women), patients with hepatic impairment, renal impairment, poly‐pharmacy, comorbidity, and frail elderly patients.30 |
| Diagnostic radiopharmaceuticals | Due to lack of appropriate animal models, phase 0 used for selection amongst four 18F‐labelled PET amyloid imaging agents for assessment of β‐amyloid plaques in brains of patients with Alzheimer's disease.31 |
| Emerging applications | |
| PBPK, M&S | Modeling and simulations incorporating in‐silico, in vitro, PBPK/PD32 and economic parameters13 can all enhance the predictive value and feasibility of phase 0 studies.22 |
| Biologics | Small antibody (PET)33. Large protein (AMS).34 |
| Adaptive design phase 0/phase I | Microdosing/phase I adaptive design.34 |
| Intra‐Target Microdosing (ITM) – drug development in target. | Intra‐Arterial Microdosing (IAM) proof‐of‐concept in rats.15 Insulin injected intra‐arterially caused local effect (18F‐FDG uptake into muscle) while systemic exposure was at microdose levels with no effects. |
| Extreme environments | Space (micro‐gravity, radiation, altered chronobiology), north/south poles (cryo‐environments, altered chronobiology), hyper/hypobaric environments (e.g., high altitudes). Altered physiology and pharmacology may have drug efficacy and toxicity implications and requires testing of pharmaceuticals in the extreme environment setting. Lack of emergency facilities favors phase 0 approaches. |
| Individualized therapy phenotyping | Prediction of DDI in healthcare settings by using microdose probes prior to initiation of therapy.22 , 35, 36, 37, 38 |
| Environmental toxins | Describing the disposition of potential carcinogens (e.g., PAH) using nontoxic microdoses in humans.39, 40 |
PK, pharmacokinetics; BA, bioavailability; PD, pharmacodynamics; TMDD, target‐mediated drug disposition; DDI, drug‐drug interactions; PBPK, physiologically‐based pharmacokinetics; M&S, modeling and simulation; PBMCs, peripheral blood mononuclear cells; FDG, fluorodeoxyglucose; PAH, polycyclic aromatic hydrocarbon.