Chandra, Nick et al It is worth noting that while three samples won't support a 4 parameter model if all patients contribute these samples at exactly the same time (i.e. the patients are exchangeable from a design perspective) this is not necessarily the case if the design is optimized to learn about the PK.
We have designed and conducted a number of studies where the number of samples is less than the number of parameters and achieved good results. Some of the issues that you need to consider are: 1) Your design will probably lead to some shrinkage in the empirical Bayes estimates which may be problematic if you intend to use the EBEs for inferential purposes. However if you're after the population estimates only (which is often the case) then this is not an issue. 2) Your design is unbalanced with respect to covariates. Adults are providing much more information about the model and parameter values than the children (even if the design in children was optimized) - which will affect your ability to identify some covariate relationships with accuracy. This can be assessed relatively easily using both optimal design and simulation based investigations. Regards Steve -- Professor Stephen Duffull Chair of Clinical Pharmacy School of Pharmacy University of Otago PO Box 913 Dunedin New Zealand E: [EMAIL PROTECTED] P: +64 3 479 5044 F: +64 3 479 7034 Design software: www.winpopt.com > -----Original Message----- > From: [EMAIL PROTECTED] > [mailto:[EMAIL PROTECTED] On Behalf Of Chandrasekhar Udata > Sent: Thursday, 29 May 2008 9:16 a.m. > To: nmusers@globomaxnm.com > Subject: Re: [NMusers] Sparse (pediatric) and rich (adult) data > > Thank you Nick and Leonid for your comments. > > Follow-up question: > I do understand that 3 samples per subject may not support 4 > parameters model. However, historically, the compound showed > bi-phasic characteristics (in adults) and I do like to use > the same model in pediatrics. Also, the model (ADVAN3, > TRANS4) did converge with no issues/errors (with pediatric > data alone). Is there something I am missing? or is TRANS5 > (AOB, ALPHA, BETA) an alternative for such limited data? > > Regards, > - Chandra > > >>> Nick Holford <[EMAIL PROTECTED]> 5/28/2008 1:38:07 PM >>> > > Chandra, > > With such a small sample its hard to learn much about > differences between adults and children. Your principled > approach using allometric scaling is a reasonable way to > bridge the gap in recognizing that adults and children are > all the same species (see reference below). > > "Children are just small adults" > > I would not be too worried about individual parameter > estimate in children being different. With only 3 samples per > child and a 2 cmt model requiring at least 4 parameters you > will always get different results if you use different assumptions. > > Nick > > Anderson BJ, Holford NH. Mechanism-Based Concepts of Size and > Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol. > 2008;48:303-32. > > > Chandrasekhar Udata wrote: > > Hi, > > > > I am working on a pop PK model to estimate PK parameters in > pediatric > > and adult patients. Pediatric study (n=20, age <6 yrs) has fewer > > samples (3) per subject whereas the adult study (n=50, > median age 20 > > yrs) has 12 samples per subject. A two-compartment model best > > describes the data for each data set. Although a > two-compartment model > > best describes the combined data, the individual parameter > estimates > > in pediatric population are different compared to those obtained > > using with pediatric data alone. Note that the parameter > estimates in > > adults were not significantly altered with either combined or adult > > data alone. Body weight is the only covariate included in the model > > with allometric exponents fixed to 0.75 on CL and 1 on V1. > > > > I would like to hear your thoughts on this and any > suggestions on how > > to proceed with modeling combined data from pediatric and > adult studies. > > > > Regards, > > - Chandra > > > > -- > Nick Holford, Dept Pharmacology & Clinical Pharmacology > University of Auckland, 85 Park Rd, Private Bag 92019, > Auckland, New Zealand > [EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090 > www.health.auckland.ac.nz/pharmacology/staff/nholford > > > >
