# PharmPK Discussion - Use of Cav in bioequivalence

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• On 16 Sep 2013 at 11:48:51, Charlie Brindley (charlie.brindley.aaa.KINETASSIST.COM) sent the message
`We are conducting a bioequivalence study with two formulation strengths.Each formulation is administered over a 21-day or 28-day dosing period.In order to compare AUC at steady state, we have proposed using Cav as the primary parameter.FDA have recommended to divide the 21-day and 28-day regimens into sub-groups and compare AUCseparately.Is anyone aware of anything published that uses Cav to compare exposure?Any arguments against using Cav is this context?Thanks,CharlieCharlie BrindleyKinetAssist Ltd`
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• On 16 Sep 2013 at 23:36:18, atish_azad.-a-.YAHOO.COM sent the message
`Dear Charlie,I guess you are looking for comparision of steady state PK parameter.Since you are using AUC at steady for comparision, I would recommend use Cmaxss for comparisioninstead of Cav.Your assumption ideally at steady state would there is no change in trough and peak concentrationafter a certain timepoint. Therefore your Cmax at steady state should vary much and most probablyvariability would also be less (I am not sure), in my opinion you must think of using Cmaxss forcomparison instead of Cav.Kindly let me know what do you think.Regards,Atish[How are you calculating Cav (or Cavss)? AUC / tau? - db]`
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• On 17 Sep 2013 at 09:04:35, helmut.schuetz.-a-.BEBAC.AT sent the message
`Hi Charlie,> We are conducting a bioequivalence study with two formulation strengths.> In order to compare AUC at steady state, we have proposed using Cav as the primary parameter.> Any arguments against using Cav is this context?>I guess you will calculate Cav as AUCss/tau? By applying a constant to a PK metric you will getexactly (!) the same T/R-ratio and its CI. Why do you want to make oranges out of apples?Helmut--Ing. Helmut SchuetzBEBAC - Consultancy Services forBioequivalence and Bioavailability Studies1070 Vienna, Austria`
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• On 17 Sep 2013 at 10:19:48, Charlie Brindley (charlie.brindley.aaa.kinetassist.com) sent the message
`Hi Helmut,I should have emphasised that we need to compare two different formulations using two treatmentregimens (21-day and 28-day dosing intervals).It has just been confirmed that the FDA will not accept Cav because of the risk of non-stationarity(time dependency).We have evidence that the 21-day and 28-day is bioequivalent based on Cav; however, I don't thinkthe FDA would change their minds for this bioequivalence study.So, we will need to carry out bioequivalence assessment separately on the different dose regimensusing AUC0-tau.We are also comparing PK from a subcutaneous formulation (7-day dosing interval) to historical datafrom an intravenous formulation (21-day and 28-day schedules).In this case, we have no option but to use Cav. Would you agree?Regards,Charlie`
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• On 18 Sep 2013 at 16:45:23, Helmut Schuetz (helmut.schuetz.aaa.BEBAC.AT) sent the message
`Hi Charlie,> I should have emphasised that we need to compare two different formulations using two treatment> regimens (21-day and 28-day dosing intervals).>OK, no problem – if you attained steady state with both regimens.> It has just been confirmed that the FDA will not accept Cav because of the risk of> non-stationarity (time dependency).>I don't get it. Can you eleborate what you mean by "non-stationarity"?> We have evidence that the 21-day and 28-day is bioequivalent based on Cav; however, I don't think> the FDA would change their minds for this bioequivalence study.>Try it: If you are able to demonstrate BE for Cav, you will be BE forAUCtau as well. So why don't you feed the beast with the red meat it wants?> So, we will need to carry out bioequivalence assessment separately on the different dose regimens> using AUC0-tau.>See above. Shouldn't be a problem.> We are also comparing PK from a subcutaneous formulation (7-day dosing interval) to historical> data from an intravenous formulation (21-day and 28-day schedules).> In this case, we have no option but to use Cav. Would you agree?>Out of curiosity: How will you do that? Do you have the subjects’ dataor only means and/or a CI? In the former case you could run aWelch/Satterthwaite-test (see FDA’s guidance: you must not assume equalvariances). If you have only Cav, you still can calculate AUCtau asCav*tau and base the comparison on it.Helmut--Ing. Helmut SchuetzBEBAC - Consultancy Services forBioequivalence and Bioavailability Studies1070 Vienna, Austria`
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• On 18 Sep 2013 at 13:59:49, Charlie Brindley (charlie.brindley.-a-.kinetassist.com) sent the message
`Hi Helmut,We will have achieved steady state with both regimens.FDA will definitely NOT accept Cav for this study; we have discussed this possibility with them.They are concerned that the two dose regimens will not be equivalent because of the different dosingintervals; i.e. there could be an alteration in the kinetics beyond 21 days.In other words, the FDA consider that there could be a time-dependent difference in the kinetics. Iknow that this is unlikely (and we have evidence that the profiles are superimposable), but Cavsimply will not be accepted a primary parameter for bioequivalence assessment."Stationarity" is a term that describes the predictable "linear" kinetics over time. I'm not sure ifthis term is widely used.For the historical comparison, we will have AUC0-tau (and therefore Cav) for all subjects; however,how can we compare AUC0-tau when the values will be greater for the 21 and 28-day treatmentscompared to the 7-day treatment? The AUC values have to be adjusted for dosing interval to make ameaningful comparison. This is not a formal bioequivalence study but we will use a bioequivalenceapproach to compare the formulations.Regards,Charlie`
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• On 19 Sep 2013 at 09:46:38, Charlie Brindley (charlie.brindley.aaa.kinetassist.com) sent the message
`Hi Helmut,Please ignore my previous response; we can, of course, compare AUC0-tau at steady state withdifferent dosing intervals.We only need to assume linear (dose and time-independent) kinetics.I should have remembered my school teacher's maxim "think before you ink"!With apologies,Charlie`
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