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Mercy College (New York) ​all right good afternoon thank you for the opportunity to speak here today my name is Lisa Marie I'm director of operations at Pro veneer we are a consulting firm that supports both new and generic drug development and I know a number of the presentations this morning mentioned VCS bio waivers and this is an established regulatory pathway that's been in existence for almost 20 years but remains largely underutilized and so today I'd like to explore and identify and opportunities for extending applicability of bcs bio waivers spreading awareness and facilitating overall acceptance of this technique as a disclaimer I am a former employee of absorption systems and so some of the data that I'll be featuring was is from absorption systems doctors did boopathy who presented this morning was kind enough to allow me to share some of this data so bcs biopharmaceutical Asif ocation system is a regulatory framework that classifies compounds according to their aqueous solubility and intestinal permeability according to the fda bcs guidance which was issued in 1996 and revised in 2000 by Oh waivers are eligible for immediate release solid oral dosage forms that are BC s1 that are highly soluble highly permeable the EMA also enables bio waivers for class-3 compounds as highly soluble low permeability so this regulatory pathway confers significant savings in time and money specifically for generic companies when it can waive clinical by Auckland studies particularly in cases where the bio equivalent studies are are challenging or require special patient populations so in one of the talks this morning with quetiapine I was mentioned that for CNS compounds there can often be adverse drug events so also for things like cytotoxic drugs which require special patient populations all of those studies can be waived with by a waiver assuming that your compound meets the criteria and so I want to take a minute to just review the fundamentals behind this I know this was largely covered in the presentations this morning but a lot of the clients that I deal with seem to think that bio waivers are too good to be true but when you break it down into the fundamental principles it's clear that this is a logical and very sensible approach and it makes a lot of sense so the primary determinants of oral absorption are gastric dissolution aqueous solubility and intestinal permeability if your formulation is rapidly dissolving in relation to gastric emptying time then gastric dissolution is no longer rate limiting and if you're a P I has high aqueous solubility over a physiologically relevant pH range which the FDA defines as pH 1 to 7.5 solubility is no longer rate limiting and if you have high intestinal permeability then G I transit time is no longer rate limiting and so under such conditions rapid dissolution high solubility and high permeability if you're an immediate release solid oral dosage form that has adequate stability your absorption should always be complete which FDA defines as 90% or more and therefore small changes in the formulation itself should have negligible impact on bioavailability therefore it is unnecessary to run a clinical bioequivalence study so there are a number of techniques that can be employed to demonstrate high permeability for BCS classification including intestinal perfusion techniques excise tissue methodology but the most popular is the in vitro cell monolayers particularly k co2 because this is a very cost effective method and has the greatest dynamic range and it's highly reproducible so k co2 is a human colon adenocarcinoma it's an immortalized cell line it's grown for 21 to 28 days and it forms polarized monolayers so a few of the speakers this morning mentioned the trans well apparatus which is on the right side you have the pointer pair of it but for the actual permeability experiment compound is dosed on the apical side of the cell monolayer and sampled from the basolateral side at various time points to calculate an apparent permeability or path value and this assay is performed in both directions a to B and B to a the ratio of B 2 a over a to B gives us the e flux ratio and that indicates the the level of symmetry in the permeability so if the e flux ratio is close to 1 that would indicate a passive transport mechanism so now active uptake or reflux this illustration at the top of the slide here just highlights the various pathways by which a compound may turn up a filial monolayer like a co2 so through the cells via the trans cellar pathway between cells via the parasite a root or mediated by uptake or a flux transporters so a flux transporters would pump things back into the apical compartment it's important to recognize that K co2 and other in vitro test systems Express the most common intestinal you flex and uptake transporters and enzymes that would be being a typically relevant for the human intestine so there are current initiatives to expand BCS bio waivers beyond class 1 particularly for BCS 3 and some BCS to compounds that are weak acids but today what I'd like to focus on it's really asking the question are we realizing the full potential within BCS 1 and what are the next steps regarding permeability solubility and general awareness for BCS bio waivers so progress has been made in the identification of more accurate internal standards for permeability classification so in order to qualify as highly permeable a compound must be Co administered with a high permeability internal standard that has 90% or more fraction absorbed in humans in
the key co2 cells or and whatever intestinal permeability technique is employed so this graph which Sid also showed this morning the features keiko to apical debase lateral permeability versus human fraction absorbed or bioavailability so this is actual human data from the approved label or published clinical data and it plots the correlation of the in vitro versus in vivo permeability classification so the FDA guidance prescribes the use of high permeability standards such as an type Irene or metoprolol but the problem with those is that their permeability is essentially at the the 90th percentile of these compounds so it's possible and quite probable to obtain false negatives when using these standards with minoxidil or other high permeability standards you're able to achieve enhanced sensitivity and reduce the number of false negatives progress has also been made in the selection of optimal pH conditions for permeability testing so a compound may be absorbed across various segments of the GI tract or along the complete GI tract and this is expressed as local vs. average permeability so according to the FDA guidance since complete absorption is based upon 90% or more fraction absorbed this is more in line with the notion of average permeability and therefore using a single point permeability determination you could potentially miss classify a compounds permeability so for example soda law when it's compared to Motoko law appears to have low permeability although the compound does exhibit complete absorption in vivo and in fact its permeability is completely pH dependent and its absorption in the distal colon comp sites for its low permeability in the proximal GI tract so recognizing that local permeability classifications using optimized pH can provide a more accurate permeability classification is progress with BCS classification however a number of limitations still exist and perhaps the most prominent one is the current prerequisite for passive permeability so in order to qualify for a bio waiver the FDA says that a compound must exhibit passive permeability it cannot be a substrate for an uptake or a flux transporter and so the guidance states that passive permeability can be established by either clinical PK data showing dose proportionality or in vitro lack of dose dependence so here's an example of typical K co2 permeability data for these bcs permeability classification studies generally three concentrations are evaluated per the FDA guidance 110 and a hundred percent of the highest dose strength dissolved in 250 milliliters so permeability higher than a co dose internal standard minoxidil would indicate high permeability and a flux ratio less than three in this case would be indicative of passive transport so this data which would would not call for any additional clinical data showing dose linearity and it confirms the sufficiency of the test system for the BCS bio waiver an alternate data set here indicates a knee flex ratio greater than 3 at the lowest concentration and of course any active transport would be most pronounced at the lower concentrations it could be masked at higher concentrations where the transporter proteins are saturated so if this type of data were observed in this scenario the the our first response would likely be to evaluate alternate pH kin so revisiting this and determining whether an optimal pH was used based on the compounds PKA additionally the FDA guidance allows for clinical exceptions so in cases where in vitro efflux is observed if there is clinical dose proportionality data that could supersede the in vitro data so you could also apply a chemical efflux inhibitor in the in vitro system to abolish any flex mechanisms and evaluate intrinsic permeability potential so really there's been significant changing perspectives on active transport and one of the reasons that this is so antiquated is because a lot of the the transporter research has been done in the past five to ten years and the FDA BCS guidance was issued again in 1996 and and updated in 2000 and the guidance itself acknowledges that at the time it was published a criterion could not be set for reflux ratio or for active transport and that is why it limits the use of BCS by waivers to passively transported compounds but since then in 2005 for example les Bennett published stating that there's no significant transporter effects for highly permeable compounds and then from 2006 to 2012 various regulatory agencies have published guidances prescribing techniques for evaluating transporter interactions using in vitro test systems and in fact these are so reliable that negative results from these in vitro transporter evaluations preclude the need for clinical testing and these guidance is furthermore state that for BC s1 compounds transporter interactions are negligible and therefore clinical drug drug interaction studies with PGP and BC RP 2 of the intestinal flux transporters can be waived for highly permeable compounds part of the rationale for this is that it is recognize that in vitro test systems tend to exaggerate a flux k co2 for example has tighter intercellular junctions and lower tight junctions porosity than the intestinal epithelium so this as you can see here there's about five to six fold higher be flexed ratio of digoxin in K co2 versus human intestinal tissue using an ex vivo technique and so if passive permeability is much higher than carrier mediated flux then passive permeability is essentially equal to and the the total effective flux and so if we revisit this case study where a flux ratio was above three at a single concentration it begs the question does this a flux even matter if the permeability is sufficiently high to take it a step further if you were to observe in vitro a flux ratio above three at all concentrations tested and high permeability at just the mid and high concentrations should this not be sufficient to demonstrate high permeability and be eligible for a bio waiver especially because the FDA's criteria for for complete absorption is ninety percent so would it not be more relevant to base the permeability on the ten percent or a hundred percent concentration is the one percent dose even relevant when it
comes to CCS solubility classification there are also modifications that could be made to extend the applicability for other compounds so BCS solubility classification is a threshold based measurement in order to meet the criteria a compound the highest dose strength of the drug product must be dissolved in 250 milliliters or less from pH one to seven point five so and so the pH range is physiologically relevant to oral absorption temperature is rund or physiologically relevant but the BCS guidance calls for equilibrium or maximum solubility determination and so I've often confronted cases where compounds may not be stable for 24 hours but it could potentially be stable for the course of oral absorption if the T max is 1 hour and the mean intestinal residence time is 3 hours is 24 hours really relevant to oral absorption and so here's here's a case where the the solubility threshold would have been point 2 MiG's per mil the compound fails to meet the criteria at 24 hours but at a more relevant time frame may have met the conditions similarly the the ph criteria ph 1 to 7.5 again if you're t max is 1 hour is your compound ever going to encounter ph 7.5 or the pH conditions relevant to the very distal GI tract and so I mentioned that BCS file waivers remain underutilized and as time okay just just a few quick points I interface on a daily daily level with generic companies and a lot of them perceive BCS bio waivers as a risk as a competitive disadvantage one of the reasons I think that could be is this recent FDA RTR guidance refused to receive standards and the language is somewhat vague for under what circumstances they would refuse to receive a bio waiver application I think that calls for revisiting and also international harmonization so bio waivers are accepted across various international agencies but there are some differences I mentioned EMA allows for bio waivers for class 3 compounds the solubility requirements are slightly different also EMA tends to view in vitro data as complementary to in vivo data so striving for a greater international harmonization could also they'll take greater acceptance and use of file waivers so just to summarize the the main points for extending applicability would be e flex substrates updating the guidance according to current transporter science solubility conditions specifically pH and and time course and spreading greater awareness and international harmonization thank you yes these things I have heard that before but technically no that would not be acceptable because the solubility and permeability have to be intrinsic properties of the API itself Bard College, Annandale-on-Hudson.
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