Dear Salim Ansari,

I think such paper could be interesting for you before you start your work

Article Factors and Mechanisms for Pharmacokinetic Differences betwe...

Article Effect of maturation on drug disposition in pediatric patients

Article Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics

Article Evaluating renal function and age as predictors of amikacin ...

Article Developmental Pharmacokinetics in Pediatric Populations

https://www.ema.europa.eu/en/documents/presentation/presentation-blood-brain-barrier-maturation-implications-drug-development_en.pdf

Model which you want to optimize could not be easy because different populations of cells and some times cells & phys/chem mechanisms could take part in different phases of PK:

a) absorption

b) distribution

c) reabsorption

d) elimination

e) recirculation (enterohepatic for example or with saliva etc)

Of course its only "general list" of mechanisms, because still many discrete mechanisms related to many drugs are unknown. So in consequence in case of one drug full model which represent all cells which take part in PK mechanisms could be tricky. Some cells, organs take part in PK and biased PK only indirectly (chronopharmacokinetics etc), so definition of the model should be very precise. Maybe easier way to do it for many drugs is take only some cells which take part in one from (a-e) phases or one mechanism. Holistic drug model related to aging/PK, based on different population of cells not exist. Validation of such model could be possible for drugs with simple and predictable PK. For more complicated PK models (all phases are present a-e) validation of the model could be really tricky. Please remember that aging process modify cells and therefore PK related to that cells but aging changing factors which are critical but not directly related to the cells (blood perfusion, blood biochemistry, GIT changes etc etc). They can affect PK directly (phys/chem) but they are not linked with cells .... for example gastric emptying rate. Idea for structuring such model is fingerprinting all critical populations of cells and make some kind of mapping. Hope some my thoughts will be useful ... :)

Best regards

Tomasz

Dear Tomasz Grabowski

Thanks a lot for valuable advice and links.

I agree that It will not be easy to represent all PK parameters in a single cell line. Similarly, Aging is a multifactorial problem that can not be successfully induced by a single mechanism.

However, I wanted to focus on specifically metabolism aspect of PK by using stably transfected cell lines (This will solve the heterogeneity cell population problem and hopefully able measure the metabolism of drugs in an age-dependent manner). Regarding aging, I do have some ideas for examples- treatment with varying amount of UV, gamma, H2O2, etc or over-expression of telomerase. But I am not sure if this will work in mimicking the aging process. Moreover, I was also thinking to try hepatic organoid which can represent the aging in more complex tissues structure and closer to the human liver.

I will be happy to know your views on this.

Best regards!

Salim

Dear Salim,

Its sound reasonable. First part of your work probably will be stable age-changes related cell line model optimization (optimized aging model). Probably experienced biotech guys can help. Standardization of the model based on some set of well known drugs which metabolism is depended to aging in vivo could be next step. If you do it then you have nice tool for screening for example NCE.

Of course such line or lines could be quite nice tool but only for aging related to selected cells and maybe partially organ. Final conclusion how predictable is your tool/model could be available after its standardization using different drugs. Its quite nice idea, final model could be very useful in drug development process. From my point of view it looks very interesting.