Guidance on PK modeling using WNL classical modeling

Phoenix Certara Forums Modelling and Simulation
1

We have preclinical species pharmacokinetic data(rat mice and dog) of compound X.We have performed PK modeling of all data set.

Results are

  1. Rat follow 2 comartmental model (model 11 in phoenix winNonlin)- best fit
  2. Mice follow 1 comartmental model (model 3 in phoenix winNonlin)- best fit
  3. Dog follow 1 comartmental model (model 4 in phoenix winNonlin)- best fit

Now the question is which model will consider for simulation in human for PK profile prediction??

2

why not try to model all these data together to integrate all knowledge you have ?

Of course you will need to use the appropirate allometric scaling

3

Dear Sir,

Can you guide me how can i use these data together for PK modeling using WNL classic model

I already did allomertic scaling for CL and Vss prediction for human

now i want to use these predicted CL and Vss for human plasma conc. profile prediction at diffrent doses

I also want to learn PK modeling by phoenix model

Please guide me on the same

Best Regards,

Vallabh

4

HI Vallabh,

don’t be disappointed but allometric scaling relies on a lot (!!) of assumptions. Are you sure that the “best models” are not artifacts (i.e., too high LLOQ where you “see” only one compartment)? Are you sure the drug is metabolized by the same enzyme system – and to a similar extent – across species? Since you are modeling EV data, transporters may also come into play (quite different between rodents and dog). Did you administer the same dose / body weight? If not, nonlinear PK might be another reason for different models. Did you use serial sampling in mice? If yes, did you take this into account?

In many cases allometric scaling is like comparing cats and elephants by counting their hairs/cm ². Just my two cents.

5

Dear Dr Helmut,

Thanks for kind reply

you right species difference may affect metabolic pathways of drug.

I need your suggestion on below mentioned questions

“Which species(Mice,Rat and dog) absorption rate constant should be used for simulation of human Oral pharmackinetic” and why?

What is the meaning of joint fitting of preclincal data(Mice,Rat and dog) in phoenix WinNonlin PK PD modeling ?

Best Regards,

Vallabh Mahajan

6

The intestinal permeability (and fa) in rat has been correlated with human Peff and human fa (salphati 2001; JPP 2001, 53: 1007–1013; Zakeri-milani, J Pharm Pharmaceut Sci (www. cspsCanada.org) 10 (3): 368-379, 2007). There are sparse references of correlations between Mouse intestinal Peff and human Peff or Human fa but they seem to be weaker compared to rat correlations (Escribano 2012; International Journal of Pharmaceutics 436 (2012) 472–477) .

As for the Dog GI tract, though the beagle is used as a biopharmaceutical model for studying formulation differences for humans, there are marked structural and morphological differences leading to differences in permeability of drugs compared ot human and there is no literature on the intestinal Peff determination in dogs, thus such correlations are limited or absent.

Hence the best choice in such a situation is the rat ka that would be a better bet compared to mouse/ dog.

7

Dear Sir,

Thanks for kind reply with wonderful explanation

I got answer of my question

Best Regards,

Vallabh mahajan

8

Hello Vallabh,

You can use all the species data together in NLME and estimate the exponents and coeff and use this for simulating your need

Regards

Kaushik

9

Dear Sir,

Greetings!!

Thanks for kind reply. I request you to guide me how to use available data set for simulation in Phoenix NLME

Please send me one example if possible

Best Regards,

Vallabh mahajan