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Day 2 Q&A

Question 1

Question: What role does pharmacogenomics play in clinical trial design for neonates?

Answer: John Van Den Anker – In neonatal pharmacology there is a delicate balance between developmental changes based on developmental physiology; and what is known about pharmacogenetics, and the question is which trumps what at what age. we have learned a lot, There is the Metabolism element, there is also variation in mutations we can have in receptors. Ie. pantoprazole, early on as newborn it’s impossible to see if you’re a slow metaboliser or extensive metaboliser, because the developmental changes in 2C19 are more important. A few weeks later, that individual with a slow metabolising capacity can be picked out, so development wins in that respect. On the other hand, 2D6 enzyme, with tramadol, after 2 weeks you can see a difference in developmental changes based on genetic background of the individual. John Davis showed in a study that you can have certain mutations in the myopiate receptor, these mutations have less abstinence syndrome and are having a shorter stay in the hospital. Basic takeaway is that we can’t translate the knowledge we have in adults to newborn babies, we learn a lot from developmental changes in transporters. Most of the time it will still be development that trumps pharmacogenetics, but there will be exceptions

Question 2

Question: How change in physiology was factored in while performing PBPK model for neonates?

Answer: For each of the parameters, we have distributions of organ sizes and differential equations representing the different processes. With regards to neonates, we assign them an organ size based on their age and we resample, so as they are aging we are resampling from a different distribution; this is something we were able to factor in. If we didn’t account for time variation in neonates we wouldn’t have gotten as accurate predictions.

Question 3

Question: What is Ivermectin drug dosage mentioned in the slide?

Answer: Typical dose for onchocerciasis is about 150-200mpk, but most original studies had been done at higher doses, which were used for model development.

Question 4

Question: Thanks for the presentations. Karen, I guess that the relatively limited info related to pediatric physiology is even more prominent for preterm neonates, especially for the role of bile salts in absorption. Can you please provide some info on where are we in this field

Answer: There’s a lot of focus on the different aspects that can affect the absorption. For these BCS class 2 drugs the bile salt concentration is important, and even if we don’t know the precise values we can do a sensitivity analysis to look at the changes. In breast-feeding the solubility may not be an issue, but after breast-feeding ends and bile salts concentration change and it could be interesting to look at the absorption. This is an area that is being closely looked at, even at the moment in adults in terms of bile salts. We need to wait for more clinical data.

Question 5

Question: Does the lactation module account for changes in milk composition in function of time after delivery?

Answer: At the moment we are just considering exposure in milk. But in time, when you have the different milk composition that changes over the first couple of weeks (colostrum, high protein lower fat) this will need to be considered as this does have an effect.

Question 6

Question: When considering organ weights how do you account for the variability between neonates of same gestational age who may have weight variations due to SGA, IUGR , macrosomy etc?

Answer: We are able to rerun a simulation, we don’t have all of those disease cofactors built in, but we do derive a distribution of organ sizes for specific age-based data that we have from the literature. We would be able to rerun to see what impact change in liver size change has on the individual and look at this in the simulation. As such we are mimicking the disease but not actually creating it within the simulation.

Question 7

Question: From Dr. van den Anker, we heard that CL may be impacted by Gestational Age (GA). How does PBPK handle the differences in GA? Is this a pre-set parameter?

Answer: It is pre-set based on data that we’ve generated from literature, then we are able to change that over time and look at the impact of changing clearance over time as well. This relates to why it’s important to look at clearance vs distribution and assess impact.

Question 8

Question: how is the correlation in disposition of drugs in preclinical species neonates to human neonates?

Answer: Rats and humans are different, different metabolising capacity; we can learn a lot from animal models, but lamb/pig/monkey models may translate better to human beings. There have been great developments in modelling and simulation, but there needs to be interactions btw modelers and clinicians, ensure everyone is speaking the same language.

Question 9

Question: What is standard blood bind to take out of neonatal patient?

Answer: 3ml per kg, depends on timeframe. We are trying to do opportunistic sampling; modelling and simulation can assist to decrease samples and total amount of blood taken from the patient. Trying to combine with clinical sampling, easier on the patient and parents. Barry Mangum – I see a lot of programmes, a lot of adult PBPK people playing in the neonatal space, wanting 14 samples from a neonate which is not possible. JVD – also not ethical, we have the tools and the techniques not to do this anything.

Question 10

Question: PBPK and Pop PK now part of M&S paradigm in pediatrics, do you really think they are accepted?

Answer: John Van Den Anker – Yes I think so, pharmaceutical companies, regulatory agencies, academia are all convinced that it is the way to go. There is a debate about pre-term infants, but there is great work being done, impact of disease etc. still needs to come to fruition, but in general yes. If not we need to better educate.

Question 11

Question: I understand there must be limitations related to volumes withdrawn, but is there still resistance to perform PK sampling in neonates in general? (i.e., is it still a problem for study participation?)

Answer: In general no, once they agree and you explain and do minimal sampling, this is not a problem. Tanja Gruber – The most frequent concern is how much blood will be taken from the baby and will this hurt the baby. We reassure that we are not taking more volume than necessary, however some patients will decline participation. PK is so critical in this group, investigators should require PK. Barry Mangum – Typically in all studies that I do we get PK, almost always requested from a regulatory perspective.

Question 12

Question: How early should payors be engaged during the development program process if RWD is being collected? Might they help shape the protocol?

Answer: Once you create the first draft of a TPP you have an idea of how your product will fit into the marketplace. Every sponsor has a commercial engagement that evaluates third therapeutical area franchises. The research is not done in a vacuum. The pharmaceutical industry collaborates in a very meaningful way, you have nothing to lose with early engagement. The sooner you know the better, this helps refine the TPP, a win-win situation. Solange Corriol Rohou – I support this, the earlier the better. In EU you have the opportunity to have regulators and HT bodies as well.