Extrapolation of Animal Dose to Human

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This article shows how to convert from animal data to human data. By Leonid Ber M.D.  Posted January 9, 2012.

If only animal experimental data is available for a given compound, it is reasonable to ask what the comparable human dose might be for the same compound. This problem is often faced by researchers when considering a new chemical substance for human trials for  the first time. The following is a discussion of how this issue is typically addressed. (1)

The process starts with estimating Maximum Recommended Starting Dose (MRSD) for first-in-human clinical trials. It is based on the No Observable Adverse Effect Level (NOAEL) derived from animal toxicological studies. Once the NOAEL is known, the Human Equivalent Dose (HED) is calculated using the following formula: (2)

Human Equivalent Dose (HED in mg/kg) = Animal Dose (mg/kg) × Animal K ÷ Human Km ,

where Km is a correction factor reflecting the relationship between body weight and body

surface area. 

For a typical adult (body weight 60 kg, body surface area 1.6 m2), Km is 37. 

For the most often used laboratory animal species the average Km are as follows:

Mouse 3
Rat 6
Guinea Pig 8
Rabbit 12
Dog 20
Human Adult 37

 

To calculate the MRSD, the HED derived from NOAEL is further divided by a safety factor (typically 10) to help determine a reasonable safety ceiling and help minimize the risk of toxicity in human clinical trials.

Determination of Human Equivalent of Pharmacologically Active Dose (PAD) is more complicated and depends upon many factors such as pharmacokinetics (i.e. absorption, concentration in the target tissue, metabolism, elimination, etc.) and differs markedly among pharmacological classes of drugs and clinical indications. Although far from ideal, the calculation method described above can be sometimes utilized. However, in the case of Pharmacologically Active Dose (PAD), dividing by safety factor is unnecessary. (2) Below is an example of conversion of a hypothetical PAD from mice to human:

Pharmacologically Active Dose (PAD) in mice               5 mg/kg
Human Equivalent Dose (HED)                                        5 × 3 ÷ 37 = 0.4 mg/kg

These calculations should only be considered preliminary and cannot serve as definitive dose determination. For more detailed information, please refer to the appropriate guidelines. (2)

References:

  1. Reigner B, Blesch K. Estimating the starting dose for entry into humans: principles and practice. European Journal of Clinical Pharmacology. 2002;57(12):835-845.
  2. Services USDoHaH, Administration FaD, (CDER) CfDEaR. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Rockville, MD 2005. 

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