(FIH) trials, selecting the initial dose is one of the most important and scrutinized decisions. Too high, and you risk harm to participants. Too low, and the data may be non-informative. Regulatory authorities require this decision to be grounded in scientific rationale and supported by preclinical data. This tutorial explores the most commonly used approaches to determine the starting dose: MABEL (Minimum Anticipated Biological Effect Level), NOAEL (No Observed Adverse Effect Level), and BSA (Body Surface Area) scaling.

Why Starting Dose Matters

The starting dose determines the initial exposure level of a drug in human subjects. In early-phase studies, especially those involving novel mechanisms or biologics, the risks are high due to unpredictable pharmacodynamics or off-target effects. Regulatory guidance from FDA, EMA, and other agencies mandates the use of a conservative, risk-based dose selection strategy.

Overview of the Three Key Approaches

• NOAEL-Based Approach: Derives the human equivalent dose (HED) from animal toxicology data
• BSA (Body Surface Area) Conversion: Used to translate doses across species based on metabolic scaling
• MABEL Approach: Uses pharmacodynamic and mechanistic data to determine the smallest dose likely to have a biological effect

Each method has its strengths and limitations. The right choice often depends on the drug type, available data, and clinical risk profile.

1. NOAEL-Based Dose Selection

What is NOAEL?

NOAEL (No Observed Adverse Effect Level) is the highest dose in animal toxicology studies at which no significant adverse effects are observed. This is typically identified from 28-day or 90-day GLP-compliant toxicity studies in two species—one rodent and one non-rodent.

Calculating the Human Equivalent Dose (HED)

Once NOAEL is identified in mg/kg, it’s converted to HED using standard allometric scaling based on body surface area (BSA):

HED (mg/kg) = Animal NOAEL (mg/kg) × (Animal Km / Human Km)

For example, if the NOAEL is 50 mg/kg in rats:

• Rat Km = 6
• Human Km = 37
• HED = 50 × (6 / 37) = 8.1 mg/kg

Applying a Safety Factor

To account for interspecies differences and individual variability, a safety factor (usually 10) is applied:

Starting Dose = HED / Safety Factor

Strengths of NOAEL-Based Dosing

• Regulator-accepted and well-established
• Works well for small molecules with known toxicities

Limitations

• May not reflect human pharmacology or biological activity
• Does not work well for biologics or highly potent compounds

2. Body Surface Area (BSA) Scaling

What is BSA Scaling?

BSA-based conversion adjusts drug doses across species by considering differences in body surface area relative to weight. It assumes metabolic rate is more proportional to surface area than to mass.

BSA Conversion Factors (Km Values)

Species	Km
Mouse	3
Rat	6
Dog	20
Monkey	12
Human (60kg)	37

Use Cases

• Translating animal doses to HED in combination with NOAEL
• Dose scaling for repeat-dose toxicology studies

Strengths

• Provides consistent conversion methodology
• Supports bridging between preclinical and clinical phases

Limitations

• Does not account for drug-specific metabolism or target engagement
• Less useful for biologics, cell/gene therapies, or local delivery

3. MABEL (Minimum Anticipated Biological Effect Level)

What is MABEL?

MABEL is the lowest dose expected to produce a biological effect in humans, based on all available in vitro, in vivo, and in silico data. It is particularly important in immunomodulators, biologics, or highly potent agents.

Data Sources Used for MABEL

• Receptor binding data (Kd, IC50) from in vitro studies
• In vivo PD effects in animal models
• In silico PBPK/PD models to simulate human response
• Ex vivo assays with human blood or tissue

Calculation Example

If 10% receptor occupancy is associated with a 20% PD effect in vitro, the MABEL-based dose should target that receptor occupancy in the projected human exposure using modeling.

When to Use MABEL

• First-in-class agents
• Monoclonal antibodies or fusion proteins
• Immuno-oncology or cytokine modulators

Strengths

• Science-driven and personalized to drug mechanism
• Prevents overdose in highly potent compounds

Limitations

• Requires detailed in vitro/in vivo data and modeling
• Not always easy to justify without regulatory experience

Regulatory Expectations and Guidelines

• FDA: Accepts both NOAEL and MABEL approaches under 21 CFR Part 312
• EMA: Emphasizes use of MABEL for high-risk compounds as per the 2017 Guideline on Strategies to Identify and Mitigate Risks
• CDSCO (India): Requires NOAEL-based calculations supported by preclinical toxicology and Schedule Y guidance

Combining MABEL and NOAEL: A Hybrid Approach

Many sponsors use both approaches for risk balancing. For instance, calculate both MABEL and HED (NOAEL-based), then choose the lower of the two as the starting dose. This satisfies both pharmacology and toxicology justifications and is especially useful in high-risk or first-in-class programs.

Best Practices

• Document all assumptions and calculations clearly in the protocol and IB
• Conduct simulation studies using PBPK platforms (e.g., GastroPlus, Simcyp)
• Use in vitro to in vivo extrapolation (IVIVE) models where applicable
• Justify safety margins and escalation plans in the regulatory submission

Conclusion

Determining the starting dose in first-in-human trials is not just a mathematical exercise—it’s a strategic decision that balances patient safety, regulatory expectations, and scientific rationale. By applying robust approaches like NOAEL conversion, BSA scaling, and MABEL modeling, you lay the foundation for a safe and successful entry into human studies. Regulators expect justification, transparency, and precision—exactly what these methods provide when applied effectively.