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What dose does an animal study translate to in humans?

Human equivalent dose (HED) calculator

Converts the highest dose with no adverse effects in an animal study (NOAEL) to a human equivalent dose (HED) by body-surface-area scaling, then applies a safety factor to give the maximum recommended starting dose (MRSD) for a first-in-human trial.

When to use itUse it when planning a first-in-human trial, to check where the starting dose should sit.

Prefilled with an example: a rat study with no adverse effects up to 10 mg/kg. Change any value and the result updates.

mg/kg

The highest dose in the repeat-dose toxicity study at which no toxicity was seen.

Corrects for body size: 3 for mouse, 6 for rat, 12 for monkey and 20 for dog. Pick a species to fill it in.

37 for an adult. Usually left as is.

10 is the default in the FDA guidance. Use a larger number when toxicity is severe or irreversible.

Maximum recommended starting dose (MRSD)0.1622 mg/kg
Human equivalent dose (HED)1.622 mg/kg
MRSD for a 60 kg adult9.73 mg

An animal NOAEL of 10 mg/kg corresponds to 1.622 mg/kg in humans. Divided by a safety factor of 10, the starting dose should not exceed about 9.73 mg for a 60 kg adult. Next, check that it is not too close to the pharmacologically active dose (PAD).

How to read it (there is no single pass line)

  • Two or more species testedUse the species with the lowest HEDAs a rule, the most sensitive species sets the dose. It is not a mechanical minimum, though: you may choose another species if its pharmacokinetics are closer to humans, or if its toxicity is more likely to occur in people.
  • Safety factor of 10When the default is enoughIf the target and mechanism are well understood, and the toxicity is reversible and can be monitored, the default of 10 is commonly used.
  • Larger safety factorWhen to start lowerGo above 10 when toxicity rises steeply with a small dose increase, when it is severe or irreversible, when the mechanism predicts a strong response, or when the limits of the animal studies leave the NOAEL uncertain.
  • Compared with the pharmacologically active dose (PAD)Too close: go lowerCheck that the MRSD is not too close to the dose at which the drug starts to act (PAD). If it is, lower the starting dose further. The first dose follows whichever is lower: the toxicity-based ceiling (MRSD) or the pharmacology-based PAD.
  • Potent drugs such as antibodiesAlso calculate from the MABEL and compareFor potent antibodies whose target may differ between animals and humans, it is standard to also derive a starting dose from the minimal anticipated biological effect level (MABEL) and take the more conservative value. The TGN1412 incident of 2006 is the lesson behind this.

How it is calculated

With data from two or more species, the rule is to take the species that gives the lowest human equivalent dose (the most sensitive species), and only then divide by the safety factor. This calculator handles one species at a time.

HED (mg/kg) = animal dose × (animal Km ÷ human Km) MRSD (mg/kg) = HED ÷ safety factor

Source: Body-surface-area scaling with the conversion factors (Km) in the FDA guidance Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005), Table 1.

With your numbers

  1. HED = animal dose × (animal Km ÷ human Km) = 10 × (6 ÷ 37) = 1.622 mg/kg
  2. MRSD = HED ÷ safety factor = 1.622 ÷ 10 = 0.1622 mg/kg
  3. Total for a 60 kg adult = MRSD × 60 = 9.73 mg

Limits of this calculation

  • Body-surface-area scaling is a general rule that assumes systemic toxicity. It may not apply to local toxicity (topical products, for example) or to drugs dosed in proportion to body weight.
  • Choosing the NOAEL is itself a matter of expert judgment, and that judgment carries straight through to the starting dose.
  • The Km factors and the safety factor of 10 are representative and default values that move with the situation. This result does not set the final starting dose.
  • This calculator gives only the NOAEL-based ceiling (HED and MRSD). It does not compare against the PAD or calculate a MABEL. Treat the result as an estimate for learning.

Primary sources

Every calculator gives an estimate for learning, built on published information and primary sources. Real decisions follow the applicable guidance and expert judgment.