Phsysiological model

Van: [email protected] [mailto:[email protected]] Namens Andre Jackson Verzonden: October 5, 2015 7:18 PM Aan: [email protected] Onderwerp: [NMusers] Phsysiological model 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 ________________________________

From: Eleveld, DJ [mailto:[email protected]] Sent: Tuesday, October 6, 2015 4:30 AM To: 'Andre Jackson'; [email protected] Subject: RE: [NMusers] Phsysiological model Hi Andre, Hopefully you can see that (1) QCO=15.87*(BW)**0.75 calculates very different values for QCO compared to (2) QCO=15.87*(WT/WTstd)**0.75 unless of course WTstd is 1kg. In that case (WTstd is 1 kg) then they are exactly the same. The easiest way to separate these situations is to find out the units of the 15.87. Where does this number come from? If QCO is cardiac output (i am just guessing here) then the units should be l/min or something like that. In (1) the 15.87 is the l/min/kg but in (2) the units of the 15.87 are l/min/70kg. So for (1) a 70 kg person QCO would be 384 l/min while for (2) a 70 kg persom gives 15.87 l/min. Hopefully one of these is obviously wrong so you can pick the right one. If the 15.87 is an estimated parameter (a THETA) then it does not matter (in a mathematical functional sense) what WTstd you use. It does the change the units of the THETA you estimate. Using 1 kg seems mathematically easiest but it makes interpretation a bit harder. The advantage of using WGTstd=70kg is that the estimated THETA has an easy interpretation as the predicted QCO for a standard individual. This makes comparison between studies quite a bit easier. A simplified example for an imaginary drug: Imagine studies in children and adults and obese and they all normalize to their median weights in thier individual studies so for clearance they might find something like: (children) CL=0.314*(WT/15kg)**0.75 (adults) CL=1*(WT/70kg)**0.75 (obese) CL=1.498*(WT/120kg)**0.75 Do these look different from each other? Superficially they do. But if you use the adult equation to calculate the values for children and obese you get: (adult formula, predict 15 kg child)CL=1*(15kg/70kg)=0.314 (adult formula, predict 120 kg obese)CL=1*(120kg/70kg)=1.498 So the three formulas (children,adults,obese) are actually exaclty the same because they predict the same CL values for all weights. This is the advantage for using WTstd=70kg even if the median weight isnt close to 70 kg. I agree with Nich Holford about the theoretical scaling exponent for k values. If you are estimating values where the units are 1/time then the scaling exponent should be -0.25. warm regards, Douglas Eleveld _____ Van: [email protected] [mailto:[email protected]] Namens Andre Jackson Verzonden: October 5, 2015 7:18 PM Aan: [email protected] Onderwerp: [NMusers] Phsysiological model 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 _____