1 reply to this topic

[raghava choudary]

Hi serge,

 

Greetings.......

 

The forum has few model examples on michaelis-menten kinetics say for e,.g the difference in v_max values obtained between WNL classic model and phoenix Models using single dose data.

 

I have a question on determining the michaelis-menten parameters. Is data from single oral dose is sufficient to determine the k_m and v_max ? Or using data from different doses (single dose escalation) would give more accurate parameters ?

 

If we have data from different doses say for e.g 5, 10, 15, 50, 100 and 200 where the PK is linear at initial doses, non-linear at mid doses and again linear at high doses, can we use data from all doses to determine kinetic parameters ?

 

The k_m determined is corrected for plasma protein binding and i am trying to correlate the km obtained invitro from enzyme kinetics experiment corrected for non-specific binding (substrate depletion experiment in microsomes) ? I didn't find correlation between the values ?  Do i need to consider the hepatic inlet concentrations rather than systemic concentrations ??

 

any example on determining the parameters from data obtained at different doses would be helpful.
 

 

Thanks in advance,

 

Raghav

 

 

 

[serge guzy]

Hi serge,

 

Greetings.......

 

The forum has few model examples on michaelis-menten kinetics say for e,.g the difference in v_max values obtained between WNL classic model and phoenix Models using single dose data.

 

I have a question on determining the michaelis-menten parameters. Is data from single oral dose is sufficient to determine the k_m and v_max ? Or using data from different doses (single dose escalation) would give more accurate parameters ?

 

If we have data from different doses say for e.g 5, 10, 15, 50, 100 and 200 where the PK is linear at initial doses, non-linear at mid doses and again linear at high doses, can we use data from all doses to determine kinetic parameters ?

 

The k_m determined is corrected for plasma protein binding and i am trying to correlate the km obtained invitro from enzyme kinetics experiment corrected for non-specific binding (substrate depletion experiment in microsomes) ? I didn't find correlation between the values ?  Do i need to consider the hepatic inlet concentrations rather than systemic concentrations ??

 

any example on determining the parameters from data obtained at different doses would be helpful.
 

 

Thanks in advance,

 

Raghav

Dear Raghav

I made an example with does from 10 to 10000.

here are the rules.

1: Km must be in the bulk of  the data concentrations

2: It will be very difficult if not impossible with one dose level to estimate both Km and vmax because with one dose level, you usually will not see the different kinetics that enable to estimate these parameters. I mean first order elimination at low dose, mixed order at middle dose and zero order (not first order) at high dose when you get saturation and you eliminate at the vmax rate.

 

I made an example and ran it with QRPEM with bad initial values for the model parameters. The program still estimated all parameters very precisely and accurately (no bias).

 

If you take my example and sort by dose level (doses per patient are 10,100,1000,10000 and then again the same cycle for the remaining patients, you will see that you cannot estimate vmax and Km.

 

At each dose, you cannot see all the 3 patterns and vmax and Km are then confounded which means that you can estimate only the ratios usually but not each model parameter separately.

 

If you have one dose level but huge variability in exposure then sometime you will be lucky and able to differentiate between vmax and Km.

Note that winnonlion used before Km in amount and not concentration.

The Phoenix interface uses KM in concentration units.

Then check before comparing the old winnonlion. I suggest you to sue only Phoenix modeling language.

We do not support anymore the old language and the new engine is way better.

best

Serge

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