Guide to Animal-to-Human Dose Scaling

About this Calculator

The Animal-to-Human Dose Scaling calculator is an essential tool in translational medicine, designed to estimate the Human Equivalent Dose (HED) from data obtained in animal studies. It uses a method recommended by the U.S. Food and Drug Administration (FDA) that relies on Body Surface Area (BSA) normalization, which is considered more accurate than simple weight-based scaling for interspecies dose conversion.

What This Calculator Does

This tool performs two primary functions based on established allometric scaling principles:

• Forward Calculation: It takes a known dose administered to a specific animal species (e.g., in mg/kg) and converts it into the equivalent dose for a human (the HED), also in mg/kg.
• Reverse Calculation: It allows you to start with a target dose in humans and calculate the equivalent dose that should be administered to an animal species to achieve comparable systemic exposure. This is useful for designing preclinical efficacy or toxicology studies.

When to Use It

This calculation is a critical step in early-stage drug development, particularly when planning for First-in-Human (FIH) clinical trials. Its primary uses include:

• Determining the Maximum Recommended Starting Dose (MRSD) for Phase 1 clinical trials based on No Observed Adverse Effect Levels (NOAELs) from animal toxicology studies.
• Translating effective doses from animal efficacy models to predict a potentially therapeutic dose range in humans.
• Guiding dose selection for further nonclinical safety studies.

Inputs Explained

• Animal Species: The species used in the preclinical study. The calculator contains pre-set K_m factors for common laboratory animals.
• Custom Animal K_m Factor: If your animal species is not listed, you can select “Custom” and enter its K_m factor (the ratio of Body Weight to BSA).
• Animal Weight: The average body weight of the animals in the study. Ensure the units (g or kg) are correct.
• Administered Animal Dose: The dose given to the animal, typically from a toxicology (e.g., NOAEL) or efficacy study.
• Target Human Equivalent Dose (HED): Used in “Reverse Calculation Mode,” this is the desired human dose you want to find an animal equivalent for.
• Human Weight: The standard reference weight for an adult human, typically 60 or 70 kg, as per regulatory guidelines.

Results Explained

• Human Equivalent Dose (HED): The primary result, expressed in mg/kg. It represents the dose in humans that is expected to provide the same level of systemic exposure as the dose given to the animal.
• Total Dose for Human: This is the HED (mg/kg) multiplied by the specified human weight (kg), giving a total dose in milligrams (mg). This is the practical amount of the drug for a single administration to an average adult.
• K_m Factors: The calculator displays the K_m factors for both the selected animal and for humans, which are central to the BSA-based conversion formula.

Formula / Method

The calculation is based on the FDA’s recommended formula for converting doses using Body Surface Area (BSA). The K_m factor simplifies this by representing the ratio of body weight to BSA for a given species.

For reverse calculations, the formula is rearranged:

Step-by-Step Example

Let’s calculate the HED for a drug tested in mice.

1. Identify Inputs:
   • Animal Species: Mouse
   • Animal Dose: 50 mg/kg (e.g., the NOAEL)
   • Human Weight: 70 kg
2. Find K_m Factors:
   • Mouse K_m = 3
   • Human K_m = 37
3. Apply the Formula:
   • HED = 50 mg/kg × (3 / 37)
   • HED ≈ 4.05 mg/kg
4. Calculate Total Human Dose:
   • Total Dose = 4.05 mg/kg × 70 kg
   • Total Dose ≈ 283.5 mg

The estimated safe starting dose for a 70 kg human would be approximately 4.05 mg/kg, corresponding to a total dose of 283.5 mg.

Tips + Common Errors

• Double-check units: A common mistake is mixing up grams (g) and kilograms (kg) for animal weight, or micrograms (µg) and milligrams (mg) for dosage.
• Use the correct K_m: Always ensure you are using the standard, agency-accepted K_m factor for the species. If using a custom factor, it should be well-justified.
• Understand the limitations: BSA scaling is an estimation. It does not account for species differences in drug metabolism, protein binding, or target receptor affinity, which can also significantly affect outcomes.
• Don’t confuse HED with the final dose: The calculated HED is a starting point. Further safety factors are often applied, and the final clinical dose is determined by a comprehensive review of all nonclinical data.

Frequently Asked Questions (FAQs)

1. What is a K_m factor?
The K_m factor is a conversion constant for a given species that relates body weight to body surface area. It is derived from the formula K_m = Body Weight (kg) / BSA (m²). It simplifies dose scaling calculations.

2. Why is BSA scaling preferred over simple weight-based (mg/kg) scaling?
Many physiological parameters, including metabolic rate, cardiac output, and renal clearance, scale more closely with body surface area than with body weight across different species. Therefore, BSA-based dose scaling generally provides a more accurate prediction of equivalent drug exposure.

3. Where do these K_m factors come from?
The K_m factors used in this calculator are based on standard values published in the U.S. FDA’s 2005 guidance document for industry on estimating safe starting doses in clinical trials.

4. Can I use this calculator for any type of drug?
This method is most applicable for systemically acting small molecule drugs and some biologics. For certain therapies, like topical drugs, cell and gene therapies, or some monoclonal antibodies with target-mediated clearance, other scaling methods may be more appropriate.

5. What does the “Reverse Calculation Mode” do?
It allows you to determine the required dose in an animal that would be equivalent to a specific target dose in humans. This is useful for designing animal studies to test the efficacy or safety of a dose range relevant to the intended clinical application.

6. What if my animal species isn’t listed?
You can use the “Custom” option in the species dropdown. You will need to find a scientifically validated K_m factor for that species from literature or calculate it if you have reliable body weight and BSA data.

7. How accurate is this HED calculation?
It is an empirically derived estimation and serves as a crucial starting point. While it is the regulatory standard, the actual pharmacokinetics in humans can vary. It is a tool for risk mitigation, not a guarantee of equivalent exposure.

8. Is the HED the final dose used in human trials?
No. The HED derived from the animal NOAEL is used to determine the Maximum Recommended Starting Dose (MRSD). Often, an additional safety factor (typically 10-fold) is applied to the HED to determine the actual starting dose, ensuring a wide margin of safety for the first human subjects.

9. Why is the standard human weight set to 60 or 70 kg?
These are standard reference weights used in regulatory submissions to ensure consistency and comparability across different drug development programs. The FDA guidance specifies using a 60 kg standard, while 70 kg is also commonly used in practice.

10. Can I apply this to pediatric populations?
No, this method and its K_m factors are specifically for converting doses to adult humans. Pediatric dose calculations are far more complex and require specialized models that account for developmental changes in physiology.

References

1. U.S. Food and Drug Administration (FDA). (2005). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Retrieved from fda.gov
2. Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of basic and clinical pharmacy, 7(2), 27–31. doi.org/10.4103/0976-0105.177703
3. Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 22(3), 659–661. doi.org/10.1096/fj.07-9574LSF

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