RE: VD as a fraction of another VD

From: [email protected] To: [email protected]; [email protected] Subject: RE: [NMusers] VD as a fraction of another VD Date: Wed, 23 May 2012 11:45:56 +0200 Dear Orlando, There are multiple models available for morphine in children younger than three years. The model by Knibbe is based on a data-driven analysis, which causes this model to be empirical, but supported by the data. In addition to that and very importantly the Knibbe model is the only model that was proven to have accurate model performance in extensive internal and external validation procedures. (Clin Pharmacokinet. 2011 Jan;50(1):51-63 & Pharm Res. 2011 Apr;28(4):797-811) Based on the available data, it was not possible to determine the distribution volume of the metabolites in the model. This would require data on the metabolites after direct intravenous infusion of the metabolites, but this is unethical and therefore not possible in children. We were therefore bound to include assumptions in our model. We have chosen to estimate the distribution volumes of the metabolites as a proportion of the central morphine compartment using the following code: V1 = THETA(1)*EXP(ETA1) ; central volume for morphine V2 = THETA(2)*V1 ; volume for M3G By using only 1 eta, we made the implicit assumption that the inter-individual variability in the volume of the metabolites is proportional to the variability in the central volume of morphine. This assumption cannot be proven or disproven with the available data, but to us it does not seem to be too unrealistic to envision that if one of the volumes increases or decreases the others will proportionally increase or decrease as well. Additionally, we found that when estimating the fraction for M3G and M6G independently, their 95% confidence interval overlapped significantly and the same was true for the distribution volume of the peripheral and central compartment of morphine. According to the rule of parsimony these parameters were therefore set to be equal. V3 = V2 ; volume for M6G equal to volume M3G V4 = V1 ; peripheral volume morphine equal to central volume For both adults and children morphine elimination through routes other than glucuronidation has been reported. In our model, with our assumptions, we found that when estimating a clearance parameter for elimination through other routes, 0 was included in 95% confidence interval of this parameter. According to the rule of parsimony we therefore did not include this parameter in the model. I would suggest that for your data you test inclusion of this parameter and decide based on statistical criteria and validation of your model whether you retain it or not. Regards, Elke From: [email protected] [mailto:[email protected]] On Behalf Of Carlos Orlando Jacobo Cabral Sent: Tuesday, May 22, 2012 6:42 AM To: nonmem users Subject: RE: [NMusers] VD as a fraction of another VD Dear Nick, I want to try a previously reported PK model (Knibbe et al. Clin Pharmacokinet 2009; 48 (6): 371-385) to fit data similar to mine of morphine and its metabolites in which the volumes of distribution of metabolites were estimated as a fraction of volume of parent drug what seems to show good estimates. But also probably I´ll try to estimate the volumes of metabolites as separate parameters THETA with its corresponding variabilities, do you have any other suggestions?, thank you. And thanks also to Bill and Rob. Kind regards, Orlando. PhD student Carlos Orlando Jacobo Cabral Departamento de Farmacología, Lab.34 Centro de Investigación y de Estudios Avanzados del I. P. N. Email: [email protected]; [email protected] --------------------------------------------------------------------------------------------------------- > Date: Mon, 21 May 2012 22:12:18 +0200 > From: [email protected] > To: [email protected] > Subject: Re: [NMusers] VD as a fraction of another VD > > Carlos, > Why? What pharmacological or physiological reason would lead you to want > to fix the volume of a metabolite to be a fraction of the parent? > Nick > > On 21/05/2012 8:19 p.m., Carlos Orlando Jacobo Cabral wrote: > > Dear NMusers, > > > > Hi, I have data of a parent drug (intravenously administered) and its > > metabolite, ¿How can I code the volume of distribution of metabolite > > as a fraction of the central volume of parent? > > An example of the model that I want to fit is: > > > > $PK > > > > V1=THETA(1)*EXP(ETA(1)) ; Central Volume of parent > > V2=THETA(2)*EXP(ETA(2)) ; Peripheral Volume of parent > > Q=THETA(3) ; intercompartmental clearance > > > > V3= ???????????? ; Volume of metabolite as a fraction of V1 with > > variability > > > > CL1=THETA(5)*EXP(ETA(4)) ; Formation clearance of metabolite > > CL2=THETA(6)*EXP(ETA(5)) ; Elimination clearance of metabolite > > CL0=THETA(7)*EXP(ETA(6)) ; Parent drug excretion by routes other than > > formation of metabolite > > > > > > > > - Thank you in advance. > > > > Orlando. > > > > /P//hD //student/ Carlos Orlando Jacobo Cabral > > > > Departamento de Farmacología, Lab.34 > > > > Centro de Investigación y de Estudios Avanzados del I. P. N. > > > > Email: [email protected] <mailto:[email protected]>; > > [email protected] <mailto:[email protected]> > > > > -- > Nick Holford, Professor Clinical Pharmacology > > First World Conference on Pharmacometrics, 5-7 September 2012 > Seoul, Korea http://www.go-wcop.org > > Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 > email: [email protected] > http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford > > >