Certain tests to answer some of the questions they we have for developing new compounds and oncology field so as outline of my presentation i’m going to talk about what did the biopharmaceutical management that we have as established workflow and pfizer inherent risks was weakly basic compounds and by form risk assessment and to case studies to talk about the
Challenges was api form and it’s some questions and challenges that we have everyday for on project team settings as how to accelerate our projects the timeline has been reduced from 10 to 11 years to only 5 years in some programs that we have and this is really challenged because we need to meet three pillars in the industries about manufacturability stability
And because it’s oncology its older route of administration’s who were talking about debug pharmaceutics so the project teams need to nominate an api form and what i mean by api form is a crystalline is it amorphous is a free form or it’s a salt or a coke crystal these all the things that we think about when we have a hit or a target molecule and what the risk of
Nominating are sold versus the free form it is time issues it’s a cost issues it’s not we need the sole to enhance something we have to calculate the risk with that and because it’s risk we need to have an assessment tools and what i’m talking about today is one of those tool that we use and it’s a smart turtle not a faster troll so we’re moving smart will and fast
At the same time so if you look at the workflows that we have and we call it end to end design end to end stop our first end starting from the hit molecule that we have and the second end would be the post approval and market launch when i’m talking when i’m talking about boy pharmaceutics the term could be new to you but it is how we have interrelationship between
The physical chemical bertie’s of a drug that dosage form or over a drug product and the route of administration that would affect the rate and extent of oral absorption so i’m focusing on oral absorption the a in ed me and we trying to focus on that because it’s oncology oncology always we’re gonna give the drug to our patients to take home we don’t have any
Patients clinical trial at least in phase one p so an hour groom will focus on the first part here when we have the preclinical stage passed and go into phase one where we ind as pas as close to be submitted there are main two question that we ask what is limiting the exposure either in animals or in humans and how we can enable this exposure of a via formulation or
Change an api form can we give the drug with food or in facet condition what would be the risks if we give it with food versus fasted when we have a package insert what would be the label for the compound when it’s marketed if the exposure is good what would be the pk parameter that would drive the efficacy is it gonna be semen or c average can we have a sustained
Release formulation to maximize exposure and turn efficacy all these questions is part of the risk assessment that we do in the biopharma pharmaceutics risk management workflow when i’m talking about specific class of compounds i’m just going to talk about the physical chemical properties of those compounds for weakly basic compounds a standard protocol in pfizer
Is to generate ph solubility on the right so on the left side here is an example of one of our compounds and as you can see it’s a weak basic compound so it has low solubility at the higher ph and higher solubility at the lower ph this is has a parent pk of 5.1 there is a difference between a parent pk and true peak aid based on the method that you used to define
The pka for this one because we’re using ability profile we quote apparent pka and as you can see there are two points here on the curve that in different color because it doesn’t fit henderson hasselbalch equation and this there’s a reason for that so these points are of interest for us this where we observe and do more experiments i’m not going to touch based
On those because it’s another lecture but what we are trying to do by understanding the ph stability profile is the concentration in solution and the bloom in the intestinal lumen that would dictate the flux through with the interior sides and then to the portal vein and what we are looking for the fraction absorbed or if a fg if you don’t have the pk a course go
Back and look at those terms fa f g and this is a term that we are interested in because this is more related to what we can change in terms of formulation api for we don’t have much handle on the metabolism of the compound or the clearance mechanism of the compound but what we can change is the formulation which can could lead to changes in the flux of the drug
Through the interior size for a weak basic compound we start by giving the drug in the stomach where its acidic ph the drug has luxury of high solubility the drug goes into the solution and progressing to the intestine where we have higher ph at this higher ph that drug crashes out of solution and precipitates out so the driving force for absorption is minimized
Because the drug is now out of solution so how much impact this physiological or physiological condition would have on the physicochemical properties of the compound how much impact we would have in reduction of the absorption there’s something that we need to test going back to what we know about bcs classification and developability pss classification as you
Know that we have four classes of compounds class two as poor solubility high permeability compound and it’s subdivided to the solution rate limited and solubility rate limited absorption and there’s formulation for these two subclasses for the solution rate limited you can reduce a particle size by jet milling or attrition milling or can form salts so you have
Higher the solution for solubility limited absorption you can have the drug in a more fast 4 min instead of crystalline form you can have lipid based formulation to change the solubility and enhance absorption so it depends on what you know about your compound that’s an example of what would happen for an api form in the form of a crisp in the form of a salt so
What happened in the salt that it would have hide fast dissolution rate and when it goes fast the solution rate it go to a state where it’s super saturating the solution beyond what we call critical super saturation and when it passes this point it’s unstable thermodynamically unstable and thanks to go to a more stable state and this starts with a process called
Nucleation where the molecules tried to come together and form nucleus and nucleus is unstable it has to be stabilized by forming a larger molecule so this happens through a crystal growth process and then at this point the concentration starts to decrease nobody can predict what happens the nucleation process is a stochastic process it cannot repeat itself even
If you have the ultimate control on the experimental condition but we can assess how risky this process is if we can do or can design the right test so if we look at what we know or what we understand about the physiology and how we can imitate that so if we go from a stomach to the intestine this is a transfer and this transfer can be done in in vitro so you can
Have a beaker with ph cl and move the contents of the beaker to another beaker was ph 6.28 and you have stomach and intestine it is simple yes is simple why don’t we do i don’t know but somebody thought about it in 1992 was the first transfer model and with the called the artificial stomach duodenum model and this was 1992 two physicians thought about what the
Effect of the histamine reducer agents on the solubility of freebase and they developed the test and this is the original publication that they have i’m not gonna go through these details but they have another enhancement of the testing in 1994 the added some enzyme to the beaker that represents the stomach and to look at the enzymatic degradation at this point
And in 2010 larry had done had done some work in enhancing the model by adding more complex steps to the model by adding pumps transfer rates other buffers same conditions non-sync conditions so complicated didn’t stop at this point there is another company called t&o developed the most sophisticated transfer model in the history of the human being and it’s
Very expensive and it’s very lengthy to run this set it takes a week to run one experiment and when we saw this and pfizer was interested in actual pfizer bought this model and to run this model it takes a week to run this model is it fast enough for us this smart turtle would be fast by doing that i don’t think so so what we did is i quoted here albert einstein
Everything should be made as simple as possible but not simpler and this what i did with the boil farm grew this is that this is the setup that we have we have an infusion pump with a syringe that has the ph condition that represent the stomach we infuse this contents to a beaker the speaker has ph of 6.8 similar to the intestine it has a ph probe to measure the
Ph and pyun system to have inline live measurement of the concentration in this beaker it’s very easy very simple you can tweak it you can make it more complex but not simpler than that because this would give you the basic condition that you need to know about supersaturation the rate of precipitation the rate of nucleation and you can use this model to look at
Your compounds i’m showing here one example of a model compound that i use called diaper demo it’s a weak basic compound pka of around 6.5 and what i’m what i’m showing on the right on the left side is a clinical trial to sample the intraluminal contents and human subjects and measure the concentration in the intestine and when i ran the model and i stumbled on
This paper i said okay what would my mother predict versus what they sampled in human trial and it was really amazing to see that we matched the rates of crystal growth that they showed or we measure the concentration over time so this means simple is not bad simple can be used in a smarter way to predict the concentration of the plasma in subjects if we put it in
The pk model and that’s what we did we use bottom of approach to predict human plasma concentration from sample and instruments building on the physical chemical properties of the compound now i’m going to go to the case studies how we use this to choose the api form so in this example we have molecule of pfizer pipeline in oncology and it’s low water solubility
Freebase and the we thought about the sole to enhance the dissolution and bioavailability of the complement so it was transitioning to pivotal phase one which means that the data from the clinical study would be used for ind it’s a weak base with 3.5 pka and trinsic solubility 30 microgram per ml solubility is high and hcl around 60 microgram per ml is not impressive
But much better moderate permeability and the projected dose is 215 meg once a day and the question is an f ip or first and patient we have what’s called single dose escalation so you give you start with a small dose based on your safety data and keep doing up what this physical property is support absorption at doses up to 1000 make of course not what would be
The solution is to change the form have higher absorption based on higher dissolution so what we did some modeling on this side to look at the fraction absorbed versus those using gastro plus at two different phs in the stomach ph 1.3 ph 5.5 so we know that from the simulation that there was there will be no ppi effect there could be food effect because we didn’t
Look at the ball salt concentration but what we did in the lab is taking this molecule and formulating a salt without synthesizing a salt and it’s very little very small trick that we do in the setup you have your freebase mix it with a solid salt and there in the syringe and infuse it and see what would happen and what would happen when we have a mesylate sulfate
Observeit cam sulphonic sol’s a supersaturation was much higher in the intestine than the freebase which gives you an indication if you take this into animal study this would be the order of the auc that you would see this is for method its salt this is for eggs obsolete this is fed condition this is fasted condition i’m listing in the middle what’s called sdd
Or a spray dry dispersion is amorphous form of the compound that we use constantly in the preclinical species to enhance exposure so our test was able to predict what would be the auc even without running any modeling or any simulation or expensive synthesis of the actual molecule the second case is very famous case in pfizer it’s about compound called a brains
It’s a breakthrough breast cancer survey and it’s a leading 5 portfolio compound and what they found that when they give the drug to a fasted population or fasting cohort the auc nc max sorry the c-max was lower than when they gave the drug to a fed population or when they used either thea need salt of the compound so we have two conditions here alvie thea need
Salt has higher exposure the freebase has to be given on a fed state condition it is a torture for cancer patients to force them to eat before having their medication this is not optimal who was talking about optimal this is not one of those so we have to change the medication this is already went through ind we cannot change the molecule but we can’t change the
Formulation so how we can do this how we can change in the formulation into enhanced exposure so this is a part of the pattern that we file this is a table where we show that the auc and the fasted condition is much lower than the fed estate at different different calorie levels of the drug the key experiment that we did is the same syringe and beaker button this
Time we have different concentration of the buffer with the buffer when you change the concentration you change the solution kinetics when you change solution kinetic kinetics you change the supersaturation probability what we notice that when we mix the powder with acetate buffer at this with different concentration we had solution versus suspension so this guv
Give give us an indication that the concentration of the buffer species would make a difference in the super saturation if we attain super saturation in in vitro we can repeat the that with the right formulation in in vivo what we did next is we repeat the same test with different buffer of solid counter ions why solid because this is going to be oral dosage form we
Cannot give iv so we did screaming of mediate succinate buffer tosylate buffer and the one who stood up was succinate buffer so if we take succinate powder mix it with the drug in a tablet what we would get we would get different formulation or different ratios of the excipient that we can do and because we can process this in different ways we can have different
Formulations so what i’m showing here is the solution test for saxena cassatt and the drug the one that stood out here the fluid bit drier formulation and it shows that it has much better dissolution profile and when we did the dissolution so when we did the cohort clinical trials we can see that this is subsonic acid tablet this is spread right dispersion this is
Another tablet was sdd this bilayer fluid bed drier oral solution we can see that we have a threshold here for the b ii if we if you cross this line your not be e if you’re above this line your b or bioequivalent so all the formulation that we have were by equivalent to the salt that we were with this was our benchmark so it worked and it was the second generation
For this formulation using a very simple technique as a summary transfer models help with bottom-up approach selection of counter and of api doesn’t need medicinal chemist to formulate the salt from the get-go also it is not a rule that souls always enhance oral absorption it’s based on what you understand about the api or the counter ion and how you administer the drug
Transcribed from video
Fady Ibrahim, ADME: Lead Characterization and Optimization, Oct 29, 2019 By GCC Research