Why scale dose by body-surface area instead of body weight?

Across species, drug-clearance parameters (metabolic rate, cardiac output, renal filtration) correlate more closely with body-surface area than body weight, so the FDA uses the Km (BSA) approach; simple mg/kg scaling over-estimates the human dose for small animals.

When should I use a safety factor higher than 10 for MRSD?

Increase the default 10x factor when toxicology raises concern: steep dose-response, non-monotonic or irreversible effects, limited PK data, or a novel mechanism with unknown human relevance.

Dose Scaling — HED & MRSD Calculator

Animal Study Parameters

Animal dose (NOAEL) mg/kg

NOAEL = No Observed Adverse Effect Level — the highest dose tested in the animal study that produced no adverse (toxic) effect, expressed per kilogram of animal body weight (mg/kg). This is normally the top-line finding from the pivotal repeat-dose toxicology study for the most sensitive/relevant species. If only a LOAEL (Lowest Observed Adverse Effect Level) is available, apply an additional safety margin via the safety factor below.

Animal species

The species the NOAEL above was derived in. Each species has an FDA-assigned Km factor (body weight ÷ body surface area) used to convert the animal dose to a human-equivalent dose on a body-surface-area basis — this accounts for the fact that smaller animals metabolise drugs faster per kg of body weight than humans do. If more than one species was tested, use the one giving the most conservative (lowest) HED, per FDA (2005).

Human weight kg

Safety factor

Human weight is the reference adult body weight used to convert the per-kg HED into a total milligram dose (default 60 kg per FDA guidance). The safety factor is the margin applied to the HED to reach the MRSD (Maximum Recommended Starting Dose) for the first human trial — FDA recommends a default of ≥ 10, increased further for steep dose-response curves, severe/irreversible toxicity, or when the point of departure is a LOAEL rather than a NOAEL.

HED (Human Equivalent Dose) normalises the animal dose by body surface area — HED = animal dose × (Km_animal / Km_human). The MRSD divides the HED from the most sensitive species by the safety factor above. Always compare the MRSD against the pharmacologically active dose (PAD) and lower the starting dose further if the PAD is lower.

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Results

Enter an animal dose and click Calculate HED to see the Human Equivalent Dose and MRSD here.

How the HED & MRSD calculation works

When a drug moves from animal toxicology into a first-in-human trial, the no-observed-adverse-effect level (NOAEL) measured in an animal species has to be converted to an equivalent human dose. The FDA's 2005 guidance standardises this with body-surface-area (BSA) normalisation, because metabolic rate and clearance scale with surface area rather than body weight. This tool automates that conversion and then applies a safety factor to recommend a starting dose.

1. Human Equivalent Dose (HED)

The animal dose in mg/kg is scaled by the ratio of the two species' K_m factors (body weight in kg divided by BSA in m²):

HED (mg/kg) = Animal NOAEL (mg/kg) × (K_{m, animal} / K_{m, human})
with K_{m, human} = 37 for a 60 kg adult.

Species	Reference body weight	K_m factor
Human (adult)	60 kg	37
Mouse	0.02 kg	3
Rat	0.15 kg	6
Rabbit	1.8 kg	12
Monkey	3 kg	12
Dog	10 kg	20

2. Maximum Recommended Starting Dose (MRSD)

The HED is divided by a safety factor (default 10, raised when there are specific safety concerns) and can be expressed as a total dose for a reference 60 kg adult:

MRSD (mg/kg) = HED (mg/kg) / Safety factor
Total starting dose (mg) = MRSD (mg/kg) × 60 kg

Worked example

A rat study gives a NOAEL of 50 mg/kg. Converting to a human equivalent:

HED = 50 × (6 / 37) = 8.1 mg/kg
MRSD = 8.1 / 10 = 0.81 mg/kg
Total starting dose = 0.81 × 60 = ≈ 49 mg for a 60 kg adult

Reference: FDA (2005), Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.

Frequently asked questions

Why scale by body-surface area instead of body weight?

Across mammalian species, many physiological parameters that govern drug clearance — basal metabolic rate, cardiac output, renal filtration — correlate more closely with body-surface area than with body weight. Simple mg/kg scaling systematically over-estimates the human dose for small animals, which is why the FDA adopted the BSA (K_m) approach.

When should I use a safety factor higher than 10?

The default 10× factor is increased when the toxicology profile raises concern — for example steep dose–response curves, non-monotonic toxicity, serious or irreversible effects, limited PK data, or a novel mechanism with unknown human relevance. The factor is a risk-management decision documented in the IND.

Which species should the HED be based on?

Regulators generally expect the HED to be derived from the most sensitive appropriate species — the one giving the lowest HED — unless there is a scientific justification (e.g. a species known not to be pharmacologically relevant) for choosing another.