PharmPK Discussion - Pharmacokinetic (Scientist)

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• On 26 Apr 2003 at 02:19:03, "letasso" (letasso.at.bol.com.br) sent the message
`I have a problem to discuss some of my results when Iused the Scientist (Pharmacokinetic Program) to fit myset data (when oral administration was used). A twocompartment open model was used to fit the data.Statistic showed a MSC value over 2 with fator 1. Thefit was very good with a good correlation .IndVars: TDepVars: cParams: a,b,d,alfa,beta,deltaC=(a*(exp(-alfa*t)))+(b*(exp(-beta*t)))-(d*(exp(-delta*t)))C is the same that A+B, C>A>B, gama>alfa>betaAfter least Squares fit the values of A and C were verylarge and almost the same, very different from themiddle values obtained.C = A+B must be always true???What can I do?Any help that you could provide would be greatlyappreciated.Best Regards,Leandro TassoLaboratório de FarmacocinéticaPrograma de Pós Graduação em Ciências FarmacêuticasUniversidade Federal do Rio Grande do SulAv. Ipiranga, 2752, 90610-000Porto Alegre-RS/BrasilFone: +55-51-3316-5215e-mail: letasso.-a-.bol.com.br`
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• On 28 Apr 2003 at 15:05:09, "Hans Proost" (j.h.proost.-a-.farm.rug.nl) sent the message
`The following message was posted to: PharmPKDear Leandro Tasso,You wrote:> IndVars: T> DepVars: c> Params: a,b,d,alfa,beta,delta> C=(a*(exp(-alfa*t)))+(b*(exp(-beta*t)))-(d*(exp(-> delta*t)))> C is the same that A+B, C>A>B, gama>alfa>beta> After least Squares fit the values of A and C were very> large and almost the same, very different from the> middle values obtained.> C = A+B must be always true???I trust that you mean 'd' instead of 'C' here since C refers to theconcentration? The minus sign in the equation suggests that 'delta' istheabsorption rate constant (ka)?In my experience it occurs rather often that ka and k (in case ofone-compartment) or alpha or beta (in case of two compartments) becomealmost similar. As a results their coefficients a (or b) and d becomeverylarge, since this value is a composite value that can written asF.Dose/V .ka/(ka-k) (or a slightly different equation for two compartments).I wrote a message to the PharmPK group several years ago, but i did notgeta fully satisfactory response. From Monte Carlo simulation I learnedthatthis happens rather often, also in cases where the true values for kaand k(or a or b) differ by a factor of, say, 2. Please note thatcomputationalproblems may at least affect the problem. If ka and k are almost equal,bothparameters become strongly correlated, and cannot be estimatedaccurately.But reparametrization does not solve the problem.I still do not know why this happens so often. Any suggestion iswelcome!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 1 May 2003 at 01:24:35, "Christopher A. Thornton" (cthornton.at.micromath.com) sent the message
`The following message was posted to: PharmPKDear Dr. Tasso,I read your post recent post regarding Scientist and forwarded the datayou provided to our technical support team.  They have confirmed yourinitial result (i.e. the convergence and solution you have inquiredabout).  After taking the following actions to adjust the initialparameters as follows we they have obtained the following results whichappear to be more consistent:If you edit rat3.par to reflect initial estimates corresponding to themiddle.par (A = 4.3106, B = 1.7903, D = 6.1294, ALFA = 0.65985, BETA =0.070391, KA = 3.3189) and then perform a fit, you end up with fittedestimates of A = 5.0608, B = 0.45005, D = 5.4789, ALFA = 0.26611, BETA =4.4382e-17, KA = 6.5629. This seems more in line with what is accepted.Ofcourse, the BETA value suggests that the concentration B is nearlyconstant. But looking at middle.par, we see that BETA = 0.070391, so anear zero value seems within tolerable experimental error.It appears that your initial paramerter estimates converged on asolutionthat is physically unlikely.  We will look at putting some additionalvalidation routines into our new version of Scientist (MicroMathScientist3.0) scheduled for release this fall.Thank you for your business.Christopher A. ThorntonManager, MicroMath Research1710 South Brentwood Blvd.Saint Louis, Missouri 631441.800.942.6284www.micromath.com`
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