12 replies to this topic

[LawrenceW]

My understanding of converting an mouse oral dosage to a human oral dosage is that as a general rule you multiply by 3 and then divide by 37.

 

For example a 500 mg/kg oral mouse dosage would be equivalent a 40.54 mg/kg oral human dosage. Is this the correct way to analyze this or is there a better more precise way to convert the dosage?

 

Table 1

Human equivalent dose calculation based on body surface area*

Edited by LawrenceW, 18 December 2017 - 07:49 PM.

[Michael]

The HED method is not really intended to estimate the most probable equivalent dose to that used in a given study, but to determine the maximum recommended starting dose (MRSD) based on the no observed adverse effect levels (NOAEL) in animal studies. Arguably direct allometric scaling of the actual dose used and the actual masses of the animals yields a better estimate of a pharmacodynamically-equivalent dose. This is done using Kleiber's allometric metabolic scaling law, which is that metabolic rate in mammals (and thus a remarkable range of stuff governed thereby, including the toxic and biologically effective doses of bioactive compounds, and even lifespan) scales to the negative one-quarter power of mass — tho' this works best for agents that are eliminated mainly by hepatic metabolism or by metabolism plus renal excretion, whereas scaling to negative 1/3 might be better for agents that are eliminated mainly by renal excretion. There's a nice allometric scaling calculator available online.

[sensei]

Allometric scaling is fundamentally flawed with respect to many substances, and almost all poisons.

 

Molar concentration is a much better way of calculating dosage for things that work at receptors or are protein/enzyme interactive (like epigenetic agents).

 

As an example:

 

A substance silences the expression of a gene by 'docking' with a protein.  The efficacy is entirely based upon the number of protein molecules and the number of silencing substance molecules. -- Which is for most things, ENTIRELY MASS BASED -- so == molar concentration.

 

 

Edited by sensei, 13 January 2018 - 05:25 PM.

[Michael]

Allometric scaling is fundamentally flawed with respect to many substances, and almost all poisons.

 

Molar concentration is a much better way of calculating dosage for things that work at receptors or are protein/enzyme interactive (like epigenetic agents).

 

As an example:

 

A substance silences the expression of a gene by 'docking' with a protein.  The efficacy is entirely based upon the number of protein molecules and the number of silencing substance molecules. -- Which is for most things, ENTIRELY MASS BASED -- so == molar concentration.

 

That's certainly best, when you actually have sufficient information on local concentration at the target tissue  in both species (including intracellularly, for substances with intracellular targets); at minimum, plasma/blood levels can be a more reliable guide than scaling factors. Unfortunately, we often lack such information — notably, at present, we have no proper pharmacokinetic (let alone pharmacodynamic) information on NMN in humans.

[sensei]

 

Allometric scaling is fundamentally flawed with respect to many substances, and almost all poisons.

 

Molar concentration is a much better way of calculating dosage for things that work at receptors or are protein/enzyme interactive (like epigenetic agents).

 

As an example:

 

A substance silences the expression of a gene by 'docking' with a protein.  The efficacy is entirely based upon the number of protein molecules and the number of silencing substance molecules. -- Which is for most things, ENTIRELY MASS BASED -- so == molar concentration.

 

That's certainly best, when you actually have sufficient information on local concentration at the target tissue  in both species (including intracellularly, for substances with intracellular targets); at minimum, plasma/blood levels can be a more reliable guide than scaling factors. Unfortunately, we often lack such information — notably, at present, we have no proper pharmacokinetic (let alone pharmacodynamic) information on NMN in humans.

 

 

Agreed.

 

But why scale allometrically unless there is an issue with toxicity?

[Michael]

 

[Using local molar concentrations for dosing is] certainly best, when you actually have sufficient information on local concentration at the target tissue  in both species (including intracellularly, for substances with intracellular targets); at minimum, plasma/blood levels can be a more reliable guide than scaling factors. Unfortunately, we often lack such information — notably, at present, we have no proper pharmacokinetic (let alone pharmacodynamic) information on NMN in humans.

 
Agreed.
 
But why scale allometrically unless there is an issue with toxicity?

 

Because absent the above kind of data, it's the best available guide. Allometric scaling is imperfect, but is based on real laws of physiological processes, and gives a reasonable ballpark in most cases; contrariwise, it would certainly be physiologically whacko and is a classic tyro error to just straight-up extrapolate a mg/kg dose from one species to another.

[sensei]

 

 

 

 
Agreed.
 
But why scale allometrically unless there is an issue with toxicity?

 

Because absent the above kind of data, it's the best available guide. 

 

I disagree -- there is nothing definitive that proves metabolic differences between species should be used for scaling of dose.

 

Please provide a sample of peer reviewed papers that show such evidence.

 

I can provide examples that falsify allometric scaling -- namely dosage of tryptamines and phenethylamines.  Allometric scaling results in dosages in humans that are either fatal or provide no effects, depending on the substance.

[LawrenceW]

Gentlemen,

 

In your opinions, which would be the best method for converting mouse dosages of NR and NMN into human doses?

Edited by LawrenceW, 13 January 2018 - 11:11 PM.

[Michael]

 

 

Agreed.
 
But why scale allometrically unless there is an issue with toxicity?

Because absent the above kind of data, it's the best available guide.

 

 
I disagree -- there is nothing definitive that proves metabolic differences between species should be used for scaling of dose.
 
Please provide a sample of peer reviewed papers that show such evidence.
 
I can provide examples that falsify allometric scaling -- namely dosage of tryptamines and phenethylamines.  Allometric scaling results in dosages in humans that are either fatal or provide no effects, depending on the substance.

 

 
I said it was the best available guide — not that it's an infallible guide. I'm unfamiliar with the examples to which you allude, but I don't see how they could falsify it, granted the many examples (in pharmacology and elsewhere) where it clearly works — they would simply be exceptions.
 
I gave some good references here.
 

Gentlemen,
 
In your opinions, which would be the best method for converting mouse dosages of NR and NMN into human doses?

As I indicated: allometric scaling.

[sensei]

 
I said it was the best available guide — not that it's an infallible guide. I'm unfamiliar with the examples to which you allude, but I don't see how they could falsify it, granted the many examples (in pharmacology and elsewhere) where it clearly works — they would simply be exceptions.
 

 

 

https://sydney.edu.a...efsPDFs/334.pdf

 

In the above referenced paper a 4mg/kg dose given to mice elicited the expected response to MDMA

 

Allometric scaling would mean a .33mg/kg dose for humans (4/12) ( 33 mg for a 100 kilo human)-- which is not enough to elicit a threshold response in a human

 

That is what is called falsification.

[Michael]

 

I said [that allometric scaling] was the best available guide — not that it's an infallible guide. I'm unfamiliar with the examples to which you allude, but I don't see how they could falsify it, granted the many examples (in pharmacology and elsewhere) where it clearly works — they would simply be exceptions.

https://sydney.edu.a...efsPDFs/334.pdf
 
In the above referenced paper a 4mg/kg dose given to mice elicited the expected response to MDMA
 
Allometric scaling would mean a .33mg/kg dose for humans (4/12) ( 33 mg for a 100 kilo human)-- which is not enough to elicit a threshold response in a human
 
That is what is called falsification.

 

That would be called falsification, if allometric scaling were an argument in logic or mathematics, or if it were presented as a rigorous scientific hypothesis — but it is none of these things, but an empirical methodology.

 

Consider the case of weather forecasting. Weather forecasts are almost never exactly correct, but are usually reasonably reflective of what actually happens. Once in a while, however, they are wildly off. Those examples don't "falsify" the methods used in weather forecasting — they merely demonstrate that the methods are imperfect, even if they're still the best methods available.

[sensei]

 

 

That would be called falsification, if allometric scaling were an argument in logic or mathematics, or if it were presented as a rigorous scientific hypothesis — but it is none of these things, but an empirical methodology.

 

Consider the case of weather forecasting. Weather forecasts are almost never exactly correct, but are usually reasonably reflective of what actually happens. Once in a while, however, they are wildly off. Those examples don't "falsify" the methods used in weather forecasting — they merely demonstrate that the methods are imperfect, even if they're still the best methods available.

 

 

Sure they do, just like the observations of actual global temperatures falsify the climate model based hypotheses

[Slobec]

Anyway, take some betaine with it http://www.freewebs....cin_therapy.pdf