# PharmPK Discussion - WinNonlin User defined three compartment model

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• On 10 Jan 2008 at 09:45:50, "anisha mendonza" (amendonza.aaa.gmail.com) sent the message
`Hello,Can someone kindly send across a WinNonlin user defined threecompartment model for an orally administered drug.Would appreciate it.Thank youAnisha M`
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• On 10 Jan 2008 at 17:24:12, "Charlie Brindley " (charlie.brindley.aaa.kinetassist.com) sent the message
`Hi Anisha,Please find attached first-order absorption, 3-compartment dispositionWinNonlin model.(Usual disclaimers re. applicability and validity apply!)Regards,Charlie[Not attached but as text below. You may need to cut-paste, save withthe correct extensions for this to work. Received as a defangedattachment ;-) which seemed to be plain text - db]--model 20remark  three compartment model - first order input and outputremark  defined in terms of a,b,c,alpha,beta,gamma,k01remarema   no.    parameter      constant       secondary parm.rema   ---    ---------      --------       ---------------rema    1        a           dose (strip)       alpha half liferema    2        b            # doses           beta half liferema    3        c           dose 1             gamma half liferema    4       k01          time 1, etc        k01 half-liferema    5      alpharema    6      betarema    7      gammarema*************************************************************commnparm 7nsec 4pnames 'a', 'b', 'c' 'k01', 'alpha', 'beta' 'gamma'snames 'alpha_hl', 'beta_hl', 'gamma_hl', 'k01_hl'endtempdose1=con(1)a1=p(1)/dose1b1=p(2)/dose1c1=p(3)/dose1c2=-1*(a1+b1+c1)endfunc 1j=2ndose = con(2)do i=1 to ndosej=j+2if x <= con(j) then goto redendifnextred:ndose=i-1sum=0j=2do i=1 to ndosej=j+2t=x - con(j)d=con(j-1)amt=a1*dexp(-alpha*t) + b1*dexp(-beta*t)+ c1*dexp(-gamma*t) +c2*dexp(-k01*t)sum=sum + amt*dnextf=sumendsecod=con(3)d1=d*(a1*(k01-alpha) + b1*(k01-beta) + c1*(k01-gamma))k01_hl=-dlog(.5)/k01alpha_hl=-dlog(.5)/alphabeta_hl=-dlog(.5)/betagamma_hl=-dlog(0.5)/gammaendeomModel 21remark  three compartment model - first order input and outputremark  defined in terms of a,b,c,alpha,beta,gamma,k01remark  includes a lag timeremarema   no.    parameter      constant       secondary parm.rema   ---    ---------      --------       ---------------rema    1        a           dose (strip)     k01 half liferema    2        b           # doses          alpha half liferema    3        c           dose 1           beta half liferema    4       k01          time 1, etc      gamma half-liferema    5      alpharema    6      betarema    7      gammarema    8      tlagrema*************************************************************commnparm 8nsec 4pnames 'a', 'b', 'c', 'k01', 'alpha', 'beta', 'gamma', 'tlag'snames 'k01_hl', &       'alpha_hl', 'beta_hl', 'gamma_hl'endtempdose1=con(1)a1=p(1)/dose1b1=p(2)/dose1c1=p(3)/dose1c2=-(a1+b1+c1)endfunc1j=2ndose=con(2)do i=1 to ndosej=j+2if x <= con(j) then goto redendifnextred:ndose = i-1sum=0j=2do i=1 to ndosej=j+2t=x - con(j) - tlagd=con(j-1)amt=a1*exp(-alpha*t) + b1*exp(-beta*t) + c1*exp(-gamma*t) + c2*exp(-k01*t)sum=sum + max(0,d*amt)nextf=sumendsecod=con(3)d1=d*(a1*(k01-alpha) + b1*(k01-beta) + c1*(k01-gamma))k01_hl=-dlog(.5)/k01alpha_hl=-dlog(.5)/alphabeta_hl=-dlog(.5)/betagamma_hl=-dlog(.5)/gammaendEOM`
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• On 14 Jan 2008 at 09:42:55, "Hans Proost" (j.h.proost.at.rug.nl) sent the message
`The following message was posted to: PharmPKDear Anisha,You wrote: > Can someone kindly send across a WinNonlin user defined threecompartment > model for an orally administered drug.Excuse me for my critical notes, but I wonder why you need this. Do youreally have data that allow the estimation of 7 (or 8, in the case ofa lagtime) parameters from a single curve? This would require at least15-20 datapoints at appropriate time points. But more important, even in thecase thatyou can identify these parameters with a reasonable precision, youcannotinterpret the model. You end up with four exponential coefficients, butthere are always two equally valid solutions, with different valuesfor theabsorption rate constant (k01 in the code provided by CharlieBrindley), butexactly the same concentration - time profile. Usually the softwareproducesonly one solution, depending on the initial estimates or imposedconstraints(e.g. k01 > alpha). So you may get one out of two solutions, and thereis noway to get the right solution. So what is the purpose of such analysis?best regards,Hans ProostJohannes H. ProostDept. of Pharmacokinetics and Drug DeliveryUniversity Centre for PharmacyAntonius Deusinglaan 19713 AV Groningen, The NetherlandsEmail: j.h.proost.aaa.rug.nl`
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• On 14 Jan 2008 at 19:03:48, "Charlie Brindley " (charlie.brindley.at.kinetassist.com) sent the message
`The following message was posted to: PharmPKHi Hans,You are correct that there are different solutions for the model.However,if the 3-compartment disposition model is shown to be appropriate usingstatistical criteria (AIC, etc) the function can be used to simulateconcentrations (e.g. after multiple dosing). The function can also beusedas the characteristic response for deconvolution analysis.Charlie`
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• On 14 Jan 2008 at 21:02:20, "anisha mendonza" (amendonza.-at-.gmail.com) sent the message
`Hello Hans,I think that the data I have would fit a three compartment modelbetter than a two compartment model (I have a sufficient number oftime points 15 or so).I know that it would be a more complicated approach, however it wouldbe a good try. Also as Charlie mentioned I would look out for the AICand other plots.Thank youAnisha`
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• On 16 Jan 2008 at 08:48:16, "Hans Proost" (j.h.proost.at.rug.nl) sent the message
`The following message was posted to: PharmPKDear Anisha and Charles,Thank you for your replies to my provocative comment. If you havesufficient data and the 3-compartment model fits better according tocriteria like AIC, then you can use the solution for multiple dosepredictions and as a reference in deconvolution, as stated correctlyby Charles. If you do not interpret the data in a physiological way,there is no problem. However, a presentation of the data denoting oneof the exponentials as k01 is actually an interpretation that is notjustified by the data.best regards,Hans ProostJohannes H. ProostDept. of Pharmacokinetics and Drug DeliveryUniversity Centre for PharmacyAntonius Deusinglaan 19713 AV Groningen, The NetherlandsEmail: j.h.proost.at.rug.nl`
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