From the Guidelines
The recommended safety margin between animal toxicity and proposed human dose is typically a factor of 10 to 100 times the No Observed Adverse Effect Level (NOAEL). This means that the initial human dose should be at least 10 times lower than the NOAEL observed in animal studies, with higher margins often applied for more caution. For small molecule drugs, a common approach is to use a 10-fold factor to account for interspecies differences (animal to human) and another 10-fold factor for intraspecies variations (differences among humans), resulting in a combined 100-fold safety margin.
Key Considerations
- The NOAEL is the dose-level below which no statistically significant adverse effects are observed in animal studies 1.
- Regulatory agencies like the FDA and EMA generally expect these safety margins to be incorporated into first-in-human dose calculations, though the exact margin may be adjusted based on the specific drug characteristics, therapeutic indication, and target population vulnerability.
- Animal models, such as the beagle puppy model, have been used to establish NOAELs for certain drugs, such as ciprofloxacin, with a NOAEL of 10 mg/kg per day 1.
- The safety margin provides a buffer against unexpected toxicities when transitioning from preclinical to clinical studies, and is crucial because animal models cannot perfectly predict human responses to drugs, and individual humans may have varying sensitivities to medications.
Safety Margin Factors
- A 10-fold factor to account for interspecies differences (animal to human)
- A 10-fold factor for intraspecies variations (differences among humans)
- Resulting in a combined 100-fold safety margin for small molecule drugs
- Smaller margins may sometimes be acceptable for biologics or when there is extensive toxicology data.
From the Research
Safety Margin Between Animal Toxicity and Proposed Human Dose
The safety margin between animal toxicity and proposed human dose is a critical factor in determining the safe starting dose in phase I clinical trials and the no observed effect level (NOEL) for non-pharmaceuticals.
- The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clinical trials and is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicological) or undesirable pharmacological effects are observed 2.
- A margin of exposure of 1/100th the NOAEL for the most sensitive animal species tested provides adequate safety for the human conceptus 3.
- The margin of safety of a drug is defined as the ratio between toxicity in animals and safety in humans, and for intravascular contrast media, the margin of safety is traditionally the ratio between LD50 and diagnostic dose, both doses being based on body weight 4.
- Toxicokinetics, which relates systemic exposure associated with early toxic signs in animals to plasma level in man, seems the most accurate and predictive criterion for determining the margin of safety 4.
Factors Affecting Safety Margin
Several factors can affect the safety margin between animal toxicity and proposed human dose, including:
- The choice of animal species and study design 5
- The use of toxicokinetic and toxicological data to determine the dose range for animal studies 5
- The consideration of human exposure levels and the associated uncertainty and variability 5
- The use of modern concepts of pharmacokinetics and toxicokinetics, as well as method-of-action studies to determine whether animal data can be used for determining human risk 6
Determining Safety Margin
To determine the safety margin, several approaches can be used, including:
- Using a 10-fold safety factor to estimate the MRSD for pharmaceuticals in phase I clinical trials 2
- Using a margin of exposure of 1/100th the NOAEL for the most sensitive animal species tested to provide adequate safety for the human conceptus 3
- Using toxicokinetics to relate systemic exposure associated with early toxic signs in animals to plasma level in man 4