How to Choose the Right Drug Candidates for Phase 0 Clinical Trials

Why Drug Selection Matters in Phase 0 Trials

Not every drug candidate is suitable for a Phase 0 microdosing study. These trials are designed to generate early pharmacokinetic (PK) and pharmacodynamic (PD) data without therapeutic intent. Therefore, selecting the right candidates is essential to ensure that the limited scope of Phase 0 delivers meaningful and predictive insights.

A poor selection could result in undetectable data, wasted resources, or misleading development decisions. This guide walks you through the key criteria for identifying strong Phase 0 candidates.

Ideal Profile of a Phase 0 Drug Candidate

An optimal candidate for a Phase 0 study should meet the following general characteristics:

• Well-characterized in vitro and in vivo profile
• Favorable bioanalytical detectability at microdose levels
• Linear pharmacokinetics between microdose and therapeutic dose
• Non-toxic at microdose levels based on animal studies
• Clear go/no-go decision trigger after study completion

1. Pharmacokinetics and Bioavailability

The drug should exhibit predictable and measurable pharmacokinetics at low concentrations. Evaluate the following:

• Good solubility and absorption (especially for oral drugs)
• Linear kinetics to extrapolate microdose to therapeutic dose
• Not subject to extensive first-pass metabolism (unless you’re measuring hepatic clearance)
• Short-to-intermediate half-life for easier blood sampling

Low oral bioavailability, nonlinear kinetics, or unstable compounds may yield uninformative microdose data.

2. Sensitivity to Analytical Detection

The drug must be detectable at very low concentrations. Choose candidates with the following qualities:

• High plasma-to-dose ratio
• Available or feasible LC-MS/MS or AMS detection methods
• Availability of a radiolabeled version (optional for PET/AMS)

If your drug cannot be accurately measured at microdose levels, the study may produce inconclusive results.

3. Pharmacodynamics and Biomarker Availability

For PD-oriented Phase 0 studies, select candidates where target engagement or mechanistic activity can be measured. Consider:

• Availability of validated biomarkers or molecular readouts
• Receptor occupancy studies possible via PET or plasma markers
• Expected changes in gene expression or protein levels

This is especially relevant for oncology or CNS drugs, where tissue-level activity can be monitored via imaging or blood-based indicators.

4. Toxicology and Safety Profile

Microdosing studies require only limited toxicology data, but the candidate should still be demonstrably safe at proposed doses:

• Preclinical data must show no adverse effects at the proposed microdose
• Single-dose tox in at least one species is generally sufficient
• Route of administration should match planned clinical route

For biologics, additional consideration must be given to immune responses even at low doses.

5. Regulatory Feasibility

Choose a drug candidate that can meet regulatory expectations for exploratory IND (FDA), scientific advice (EMA), or Phase 0 pilot frameworks (India, Japan). Ensure the following:

• GLP-compliant preclinical toxicology data
• Stability of the compound in microdose formulation
• Feasible timeline for manufacturing and analytical validation

Complex formulations or drugs with undefined regulatory pathways may be better suited for Phase 1.

6. Development Context and Strategic Fit

Phase 0 is most useful in programs with:

• Multiple candidates competing for advancement
• Uncertainty in human pharmacokinetics despite good animal data
• High development cost and need for early de-risking

If the candidate already has established full preclinical packages and funding, going directly to Phase 1 may be more efficient.

Real-World Example: Oncology Drug Selection for Phase 0

A biotech company had two kinase inhibitors targeting the same receptor. Both had comparable efficacy in vitro, but differed in PK profiles. Using microdose administration and PET imaging, only one compound showed adequate tumor uptake in humans. The other was deprioritized, saving millions in development costs.

Common Mistakes in Candidate Selection

• Choosing drugs with poor solubility and oral absorption
• Overlooking metabolism saturation at higher doses
• Selecting molecules with no measurable endpoints
• Not confirming bioanalytical assay sensitivity beforehand

These issues often lead to failed Phase 0 outcomes or misinterpretation of early human data.

Summary for Clinical Research Students

Choosing the right candidate for a Phase 0 trial is not just about having a new molecule—it’s about aligning science, safety, and strategy. As a student or new researcher in clinical development, regulatory science, or translational research, understanding these criteria prepares you to design early-phase programs that are both informative and efficient.

When applied correctly, Phase 0 becomes a powerful tool for de-risking innovation and enhancing clinical success rates.