RE: covariates

From: "Nick Holford" n.holford@auckland.ac.nz Subject: RE: [NMusers] covariates Date: Thu, September 16, 2004 3:34 am Renee, > > Hello, Nick > > 1. My understanding of the allometric models you mentioned are as follows: > > CLi = CLstd * (WTi / WTstd) **0.75; Qi = Qstd * (WTi / WTstd)**0.75 > V1i = V1std * (WTi / WT)**1; V2i = V2std * (WTi / WT)**1 > > each parameter/covariate combination will be run in NONMEM, and OFV will be > compared with that of basic model. Since the subjects of my study are > pediatric patients, WTstd would be 70 kg. Therefore, in my scenario, WTstd > would be the media WT of the study patient cohort and (CL, Q, V)std would > be the typical value of this study population. Please comment. The allometric model you have written is correct. However, I think it is pointless to look at the OFV change compared to a model without weight. The allometric model is a priori correct as far as I am concerned. Just use the allometric model on all the parameters and get on with your life :-) You can use Wtstd=70 or some other number e.g. the median of your patients, when estimating the parameters. In theory it is better to centre the parameter estimates somewhere in the middle of the actual covariate values but I don't think it makes any big difference. However, for reporting the results I prefer to standardize all parameter values to 70 kg so that they can be readily compared to other results. > 2. There are only 40 patients in this study. Therefore, in the second > step, the stepwise/backward method will be employed to screen the other > covariates? If you only have 40 patients then the Ribbing and Jonsson paper suggest it is a waste of time to do blind searches for covariates using forward/backward step methods. If your patient population is under 1 year old then you might want to try models based on post-conceptional age to describe the maturation of development e.g. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004;92(2):208-17. Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NHG. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology 2002;96(6):1336-45 There is at least some biological expectation and empirical evidence that clearance and volume change in the first year of life. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/