# PharmPK Discussion - Determining ka from non-compartmental analyses

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• On 21 May 2004 at 19:40:44, L T (choco4evermore.-a-.yahoo.ca) sent the message
`Hi allI have a couple questions regarding non-compartmental modeling.  We wouldlike to determine the Ka of lopinavir from steady-state PK data (PKprofiles).  LPV is given orally (assumes 1st order absorption and 1st orderelimination), and all patients are at steady state.  We modeled our datausing WinNonlin 4.1, non-compartmental analyses.  Here are my questions:1.  Is it true that AUMC(0-infinity) = AUMC (tau, steady-state)?  Just like      AUC (0-infinity) = AUC (tau)?2.  from my previous studies, MRT (oral) = MRT (iv) + 1/Ka      and also                          MRT (oral) = 1/K + 1/Ka       where K is the elimination rate constant and Ka the absorption rateconstant.  Is it valid for me to calculate Ka from my non-compartmentalresults using K=lambda z, and MRT(oral) = AUMC(tau)/AUC(tau)?I would appreciate any advice in this matter.Thank you!Lillian TingUniversity of British Columbia`
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• On 25 May 2004 at 20:28:03, "Hans Proost" (j.h.proost.-a-.farm.rug.nl) sent the message
`Dear Lillian,With respect tu your question: > 1.  Is it true that AUMC(0-infinity) = AUMC (tau, steady-state)?  Justlike >       AUC (0-infinity) = AUC (tau)?No, this is not true, as can be concluded from a simple numerical example. Ican send you a spreadsheet demonstrating this. If k is large, both valuesare close to each other, since both profiles are close to each other. In'normal' cases, AUC(0-infinity) is larger than AUC(tau); e.g. for k = 0.05/h, ka = 2 /h, and tau = 24 h, the difference is about a factor 2.Consequently, the answer to your second question is also negative.Best regards,Hans ProostJohannes H. ProostDept. of Pharmacokinetics and Drug DeliveryUniversity Centre for PharmacyAntonius Deusinglaan 19713 AV Groningen, The Netherlandstel. 31-50 363 3292fax  31-50 363 3247Email: j.h.proost.aaa.farm.rug.nl`
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• On 26 May 2004 at 20:02:12, Arthur B Straughn (astraughn.at.utmem.edu) sent the message
`Hans,Have to disagree with you about being able to evaluate Ka from steady-statedata using non-compartment analysis.  I do agree that AUMC(0-inf) singledose is not equal to AUMC(0-tau) at steady-state, but it is a simplespreadsheet exercise to conduct reverse superposition on the steady-statedata to acquire single dose concentrations.  From the single dose data AUCand AUMC will give correct MRT and thus ka. There are severalassumptions/conditions however that need to be met: 1. The terminaldisposition can be determined from the steady-state data (study design mayrequire wash out data) 2. Absorption is first order (true for single doseas well but if one only wants MAT the order of absorption in notimportant).  The reverse superposition doesn't even require data to be atsteady state as long as you have characterized the dosing interval andterminal disposition appropriately with the sampling scheme.  Again you mayor may not need wash out to get K. I think there was a paper on  this topic in J. Pharm. Sci. a number of years ago.Art Straughn, Pharm.D.Professor and Director Drug Research LaboratoryDepartment of Pharmaceutical SciencesUniversity of TennesseeMemphis, TNastraughn.aaa.utmem.edu`
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• On 27 May 2004 at 19:32:44, L T (choco4evermore.aaa.yahoo.ca) sent the message
`Hi HansThanks for the input.  Could you send me the spreadsheet you mentioned so Ican take a look?Unfortunately we only have steady-state data.  Maybe there is some otherway to calculate Ka?Thanks!LillianUniveristy of British Columbia`
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• On 27 May 2004 at 19:45:18, "J.H.Proost" (J.H.Proost.-at-.farm.rug.nl) sent the message
`Dear Arthur,You wrote:>"Have to disagree with you about being able to evaluate Ka from>steady-state data using non-compartment analysis."I did not say whether or not Ka can be calculated. I said that AUMC aftersingle dose and at steady state are different. This implies that thesuggested method for calculating Ka is not correct.>"... it is a simple spreadsheet exercise to conduct reverse superposition>on the steady-state data to acquire single dose concentrations."Thank you for pointing to this method. I did not know it, and I will have alook at the reference in J. Pharm. Sci. But I have my doubts on suchmethods with respect to their accuracy and precision, apart from thenumerous assumptions that cannot be checked properly.Personally I am not in favor of noncompartmental pharmacokinetics, mainlybecause it does not allow a prediction of the time course of theconcentration. The latter is essential for relating dose to therapeuticactivity of a drug, a key issue in pharmacokinetics. In my view, theadvantage of not using a (compartmental) model does not counterbalance thisdisadvantage. What can we learn from noncompartmental pharmacokinetics? Iposed this question in the PharmPK group some time ago, but did not learn much.Best regards,Hans ProostJohannes H. ProostDept. of Pharmacokinetics and Drug DeliveryUniversity Centre for PharmacyAntonius Deusinglaan 19713 AV Groningen, The Netherlandstel. 31-50 363 3292fax  31-50 363 3247Email: j.h.proost.at.farm.rug.nl`
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• On 28 May 2004 at 16:22:26, "Art Straughn" (astraughn.at.utmem.edu sent the message
`Hans,Sorry, I just meant to disagree with the implications (not the statement),that since AUMC(0-inf) single dose is not the same as AUMC(0-Tau), then Kacould not be determined using non-compartment analysis with ss data.  I amnot a fan of "connect-the-dots" for AUMC determinations anyway because ofthe extensive extrapolation (usually 20% or more) when compared toextrapolation of AUC (5 to 10%).  As you point out, questions aboutprecision and accuracy are brought into the picture. This though, should notdistract from the value these kinetic parameters have had related toabsorption and disposition modeling.As far as which is better: "connect-the-dots" (non-compartment) vs."minimizing SSE"(compartment), it depends on what "truth" you want to gleanfrom the data.  Generally, regulatory truth requires the use of"connect-the-dots", while intellectual truth mandates the use of "MinimizeSSE". The real truth is probably somewhere in between.  Please note: I amnot implying regulators only accept "connect-the-dots" analysis as fondlyreferred to by Nick H. as Mickey Mouse Kinetics.Art Straughn, Pharm.D.Professor and DirectorDrug Research LaboratoryUniversity of Tennessee874 Union AveSuite 5PMemphis, TN  38163E-mail: ASTRAUGHN.at.UTMEM.EDUPhone: (901) 448-6033Fax:       (901) 448-6940`
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• On 28 May 2004 at 16:27:50, L T (choco4evermore.aaa.yahoo.ca sent the message
`Hi ArthurThanks for your suggestion.  Could you send me that spreadheet that doesreverse superposition on steady-state data please?  I didn't know aboutthis method and would like to give it a try.I only have steady-state data, and no wash-out period in thisstudy.  Hopefully we can still utilize such data.Thanks a lot!Cheers,LillianUniversity of British Columbia`
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