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Kindly suggest first human dose to be calculated from toxicity studies performed in animals like
Mice and Rats.
The rodent toxicity studies has given idea on safe dose through IM and IV routes in the animals.
Kindly suggest the best equation to co-relate the same i.e. animals to human dose
With best regards
Dr kurani
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Dear Dr Kurani,
As there many approaches to be followed in doses extrapolation like allometry from animals to human,
first sensitive species should be identified based on CYP profile, gastric permeability, etc. Then
NOAEL should be established in pivotal toxicity study of at least 28 day duration. The NOAEL should
then converted to (HED) human equivalent dose by dividing it by 100 (considering 10 factor of intra
species variability and 10 for interspecies).
Hope this helps.
Vishal.
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Dear Dr. Kurani, probably the follow text will help you:
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 Km ÷ 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:
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.
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.
--
Please try to get also this reference
Shannon Reagan-Shaw * , Minakshi Nihal *, † and Nihal Ahmad *, † ‡
Dose translation from animal to human studies revisited
+ Author Affiliations
*Department of Dermatology,
†Paul P. Carbone Comprehensive Cancer Center;
‡Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA
Correspondence: 1Correspondence: Department of Dermatology, University of Wisconsin, B-25 Medical
Science Center, 1300 University Ave., Madison, WI 53706, USA. E-mail: nahmad.at.wisc.edu
--
Hope this will help you
Best regards,
Sergio SB
"Dr. S. F. Sanchez Bruni"
--
Dear Dr. Kulkarni,
There is a FDA guidance which walks you through the steps outlined by Vishal. It is titled -
'Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for
Therapeutics in Adult Healthy Volunteers'.
Hope this helps,
Suresh
Suresh Kumar Agarwal
[See
2005: Guidance for Industry
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult
Healthy Volunteers
at http://www.fda.gov/downloads/Drugs/Guidance/UCM078932.pdf
2002: Guidance for Industry
and Reviewers
Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers
at http://www.fda.gov/OHRMS/DOCKETS/98fr/02d-0492-gdl0001-vol1.pdf
While searching for 'Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult Healthy Volunteers' I found
Tam, K. (2013). Estimating the “First in human” dose – a revisit with particular emphases in
oncology drugs. Admet & Dmpk, 1(4). doi:10.5599/admet.1.4.10
- db]
--
Dr. Kurani,
Here is a link to a paper that describes how to estimate the safe starting dose for human studies:
http://learnpkpd.com/downloads/estimating-the-maximum-safe-starting-dose/
Kind regards,
Nathan Teuscher
Nathan S. Teuscher, PhD
Founder and President, PK/PD Associates
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