 Good afternoon everyone and it is a great pleasure and honor to be here and I have to thank the organizers for inviting me To speak at this really distinguished meeting which we all enjoy and it's very interactive and I loved All of the presentation so far and I'm looking forward to many more anyway so the topic that I've been commissioned with is regarding how we achieve area under the curve that is satisfactory and we maintain this fine balance between Keeping the dose fairly reasonable as well as Managing to maintain optimal efficacy with balancing the toxicities in between so the Official definition of area under the curve is the integral of the plasma concentration of the agent versus an interval of definite time so here is the definition but bottom line what it means to all of us as When we are clinically facing a patient is that it allows us the measurement of the bioavailability of an agent that you're using And allows us to balance it with the efficacy and eventually toxicity So I have here in my estimate what the factors are that impact area under the curve compliance is a huge one the dose of course schedule Absorption and there are different ways of You know that there are different things that can interfere food and other drugs and Multiple other things that we've seen that have interacted with each of these agents and then of course the pharmacogenetics Pharmacokinetics of the agent can affect and have a significant amount of impact on the efficacy and the toxicity is noted and Toxasities of course which will have a huge impact on your area under the curve because if you have a significant toxicity that makes you Completely either discontinue the agent or hold it temporarily for quite a while That is again going to have an impact on your AUC so the impact of compliance which is not Frequently discussed but is huge and one of the report shows this is the actual Population data survey of the impact of compliance on medications treatment prescribed to treatment filled There is an actual prescription drop-off right there and then Eventually if you're looking at the treatment continued, which as you can see in kidney cancer We are not doing sporadic treatments anymore We are more vested in the continuous part of the treatment and treatment continued at least is seen in this 47% range so about half of the patients will be compliant with the medication now This is generally across different medications The good news is that compliance is fairly much much better in cancer patients So studies that have been specifically done in cancer patients show us That compliance with oral agents is actually very good So and these are very small very limited studies but this was a study of synitinib where patients 36 patients were surveyed and watched very carefully for their compliance and Only two patients were non-compliant and the reason for the non-compliance of course was Toxicity that they had grade three or four toxicities of some shape or form Interestingly though the other 13 patients who had these kind of severe Toxicity's or adverse events related to synitinib actually continued on the same dose So it's not absolute given and what we find is that patients who are being treated for their cancer with therapy actually stay Remarkably compliant despite in the face of significant Toxicity's so the other things of course are the who who what where when of medications in kidney cancer and One of the studies has been looking at exposure and dose response what we do know about synitinib is that the increase the increasing dose can result in better exposure and There are studies that show us improvement in efficacy with increasing dose Obviously the toxicities also go high up and it's not a direct relationship as you can see there are some people who at 50 milligrams are or even less doses have equal values of PKs or AUC as Somebody with a much higher dose of 75 milligrams of synitinib So here is the study that showed you that the time to progression as well as overall survival Was improved with increasing doses and this was a study again of synitinib done in both kidney cancer as well as GI stromal tumors basically showing you that the higher the dose the better the efficacy to a certain extent Interestingly though clinical studies are showing us that that didn't quite result in actual improvement in efficacy And as you're probably familiar with the Mozart study which compared patients with 50 milligram for four weeks on two weeks off schedule with the 37.5 milligrams Continuous schedule and if you look at the median progression free survival or overall survival for that matter It actually was no different with and maybe slightly inferior with the continuous dosing as Compared to the four weeks on two weeks off schedule Interestingly if you just look at dose intensity, it's actually somewhat higher with the 37.5 milligrams daily compared to the 50 milligram over Six weeks because if you calculate it out per daily dose it ends up being about 33 point three three so Interestingly it may not be the dose intensity But there might be a threshold that you have to hit to actually get to that efficacy end point is one of the Thinking behind why these studies are not showing you a major difference in efficacy and these the other two studies I have listed there are phase two trials that again looked at the continuous dosing and Came up with similar results that no different and definitely not better than the 50 milligram four weeks on two weeks off dose Again some more clinical data that tells us that dose escalation didn't quite get us where we wanted to be in Terms of improvement in efficacy is that sit in a dose titration study And this was a study of starting off with five milligram twice daily 213 patients were treated anybody with progression severe Toxicity's of course was taken off the study and then after that the patients who were tolerating it Okay, we're randomized to either get a skill dose escalated up to 10 milligrams twice daily versus placebo and the response rates and progression free survival as you can see here was no different and Definitely no better with the dose escalation as compared to placebo So again, there might be that threshold effect that you see have to see in terms of efficacy and then beyond that the incremental Advantage tends to be fairly small with a major increase in toxicity There are some patient populations that were found to be susceptible to Increased toxicity rates and for instance the there were PK studies that were done with synitin if that showed about 8% of the patients had had a dose PK levels that were at the same level at 50 milligrams that were seen at for instance 75 milligram doses so so there is that variation Obviously and female gender and low body weight people with a lot of weight loss tend to be the more likely people who have this kind of significant dose level increases and You know right now we don't have any good predictive markers to say upfront Who is likely to get increased risk of toxicity? So going back to the PK PD profile of targeted therapy, you know, I think it's pretty similar for any therapy Obviously in this kind of treatment because you have vested for patients who are benefiting in the longer term of therapy you're looking at the metabolism of the drug and The chances of absorption and eventual bioavailability to maintain the efficacy Effect and pharmacogenomics really there are some snips that have been reported usually in the metabolism enzymes the cytochrome P450 system That have been associated with increased risk of toxicity with synitinibis apanib and some for mTOR inhibitors as well That have been reported again. No exact correlation has been noted as yet So there are more studies should would have to be ongoing in this regard Same thing for genome-wide association studies have identified different loci that result in differences in the Accumulation rate of metabolites and the range is really very fairly wide from 10 to 60 percent Which obviously could have an impact on the toxicity rates And there is always that 8 to 10 percent of the patients that we when we start treatment Completely unpredictably have a significant amount of toxicity it within the first few weeks of therapy even So my conclusions of all of this come up with that pharmacogenetics at present There are none no real test that we can recommend that are ready for prime time in Predicting this incidence of severe toxicities in these patients the additionally the dose schedule and dose intensity and Probably hitting that threshold dose for the patient does make a difference in terms of efficacy But clinically when you look at populations or groups in randomized setting the dose escalation beyond the standard dose has not been proven to be of any improvement in efficacy and Currently we are stuck back with our optimizing targeted therapies based on our clinical factors such as response and Toxicities and that still remains the current standard. Thank you for your attention