[FORGED] Phsysiological model

2 messages 2 people Latest: Oct 06, 2015

Re: [FORGED] Phsysiological model

From: Nick Holford Date: October 06, 2015 technical
Andre, Standardizing parameters with allometric models does not bring the (minor) benefits that can be obtained by centering linear models. In fact it is easy to prove that standardizing cannot change anything except the scale of the parameter that is estimated. Thus you can use any standard value and this will not change the quality of the fit in any way. See Anderson & Holford (2011) and slide 30 & 31 in http://holford.fmhs.auckland.ac.nz/docs/tips-and-traps-in-pediatric-PKPD.pdf However, there are major advantages for humans who try to compare results from different studies if a common standard is used. A common standard for weight is 70 kg (Holford, Heo & Anderson 2013). The practice of using the median weight to standardize allometric model parameters is to be discouraged because each study will report a different parameter even if the true parameter is the same simply because the median weight varies from study to study. Be careful using allometric theory with rate constants. I don't know what K_Gutmet is supposed to describe but if it is a first order rate constant that can be predicted from a clearance/volume then the allometric theory exponent is -1/4 not 3/4 (0.75 as you have written). Nick 1. Anderson BJ, Holford NHG. Tips and traps analyzing pediatric PK data. Pediatric Anesthesia. 2011;21(3):222-37. 2. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941-52.
Quoted reply history
On 6/10/2015 6:17 a.m., Andre Jackson wrote: > All: > > I am attempting to take a Physiological model presented in the literature and place it into Nonmem with the help of the authors. A point was raised related to centering parameters which I would appreciate some feedback. > > In the published paper, model parameters such as Cardiac output are allometrically scaled as power models: > > QCO=15.87*(BW)**0.75 > > and gut metabolism as: > > K_Gutmet=THETA(2)*(WT)**0.75) > > My question is should I use these equations as stated in the publication or should I center the estimates as e.g., > > QCO=15.87*(WT/WTstd)**0.75 > > The weights that will be investigated go from 30 kg up to 80 kg. > > It would also be very helpful if one can give me an explanation as to why or why not. > > Thanks > > Andre -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 email: [email protected] http://holford.fmhs.auckland.ac.nz/ Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & Clinical Toxicology. 2014;2(2):1023-34. Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin Pharmacol. 2015;79(1):18-27.

RE: [FORGED] Phsysiological model

From: Andre Jackson Date: October 06, 2015 technical
Nick: The K_Gutmet is a first order rate constant (1/h) for gut metabolism so it is not predicted from Cl and Volume and you are correct it should have an exponent of -1/4. Thanks.
Quoted reply history
-----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Nick Holford Sent: Tuesday, October 6, 2015 1:11 AM To: nmusers Subject: Re: [FORGED] [NMusers] Phsysiological model Andre, Standardizing parameters with allometric models does not bring the (minor) benefits that can be obtained by centering linear models. In fact it is easy to prove that standardizing cannot change anything except the scale of the parameter that is estimated. Thus you can use any standard value and this will not change the quality of the fit in any way. See Anderson & Holford (2011) and slide 30 & 31 in http://holford.fmhs.auckland.ac.nz/docs/tips-and-traps-in-pediatric-PKPD.pdf However, there are major advantages for humans who try to compare results from different studies if a common standard is used. A common standard for weight is 70 kg (Holford, Heo & Anderson 2013). The practice of using the median weight to standardize allometric model parameters is to be discouraged because each study will report a different parameter even if the true parameter is the same simply because the median weight varies from study to study. Be careful using allometric theory with rate constants. I don't know what K_Gutmet is supposed to describe but if it is a first order rate constant that can be predicted from a clearance/volume then the allometric theory exponent is -1/4 not 3/4 (0.75 as you have written). Nick 1. Anderson BJ, Holford NHG. Tips and traps analyzing pediatric PK data. Pediatric Anesthesia. 2011;21(3):222-37. 2. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941-52. On 6/10/2015 6:17 a.m., Andre Jackson wrote: > > All: > > I am attempting to take a Physiological model presented in the > literature and place it into Nonmem with the help of the authors. A > point was raised related to centering parameters which I would > appreciate some feedback. > > In the published paper, model parameters such as Cardiac output are > allometrically scaled as power models: > > QCO=15.87*(BW)**0.75 > > and gut metabolism as: > > K_Gutmet=THETA(2)*(WT)**0.75) > > My question is should I use these equations as stated in the > publication or should I center the estimates as e.g., > > QCO=15.87*(WT/WTstd)**0.75 > > The weights that will be investigated go from 30 kg up to 80 kg. > > It would also be very helpful if one can give me an explanation as to > why or why not. > > Thanks > > Andre > -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 email: [email protected] http://holford.fmhs.auckland.ac.nz/ Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & Clinical Toxicology. 2014;2(2):1023-34. Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin Pharmacol. 2015;79(1):18-27.