Re: Re: question about sampling time

On 2013-10-27, at 20:14, "Nick Holford" <[email protected]> wrote: > Winnie, > Please see below for my comments and suggestions. > Best wishes, > Nick > > On 28/10/2013 8:28 a.m., Winnie Seto wrote: >> >> Hello NONMEM users and Dr. Holford >> >> I am a novice when it comes to pop PK simulations- >> > You refer to pop PK simulations but what you describe below sounds more like > a plan for a pop PK parameter estimation study rather than a pop PK > simulation study. Of course, some simulation would be helpful for planning a > parameter estimation study (see below). > > It would be helpful for know what your objectives are. There must be hundreds > of published aminoglycoside studies so why are you planning another? What are > you hoping to learn? Do you have a hypothesis you want to confirm? If you > don't have a clear idea about what you going to learn or confirm, and a > scientific plan to show you can achieve the objectives, then I would consider > this kind of study unethical. >> >> Our group is planning on a prospective once daily aminoglycoside >> pharmacokinetic study in patients with proposed serial time levels post dose >> with 30min, 2hr, 4hr, 12hr and 24hr post dose drug levels. >> > In typical patients given once daily doses of aminoglycosides such as > gentamicin it is most likely that a 24 h concentration would be less than the > limit of quantification of you laboratory. IMHO a 24 h sample would be > unethical in a typical patient over the age of 1 year because it has some > discomfort and probably $$ cost for the patient and is of almost no value. > This is where some simulation could be helpful. In patients with low > clearance (e.g. due to immaturity in neonates) then a 24 h sample might be > reasonable. You can see a simple simulation example here in slide 17: > http://holford.fmhs.auckland.ac.nz/docs/target-concentration-intervention.pdf > This kind of simulation is easily done in Excel. Just doing it yourself will > help you understand the answers to many questions about PK study design. > >> We will have only a small sample size (less than 50 patients) and some >> patients may not be able to have samples at all these timepoints from >> logistical reasons. >> > The sample size depends on what your objectives are. 50 patients would be > fine to describe the popPK of an aminoglycoside given 5 conc measurements per > subject. If your objective is related to a question about covariates > predicting variability (weight, renal function, maturation, etc) then you may > need a larger sample to get a clear answer. >> >> I would really appreciate some advice on the following: >> >> 1.Is there a number of minimum patients that I need for each sampling time >> point for pop pk analysis? >> > This kind of question about the number of patients, number of samples and > timing of samples is best answered by using an optimal design program. See > http://www.page-meeting.org/pdf_assets/9481-mentre_page07postPage2.pdf for a > review. Most of these programs will have improved since then but some of them > are no longer available). The trade off between these design quantities will > be determined by what your objectives are and how much money and time you > have. >> >> 2.For each time point – is it better to have some variability within the >> sampling time window e.g. 10-12hr with a few patients with samples >> distributed at 10, 11 or 12 hour mark? >> > Yes -- as a general rule your design will be more robust if you use sampling > windows and in real life samples will not be taken at exactly the same time > in every patient. For data analysis it is essential to record the dosing and > sampling times as accurately as possible. >> >> 3.I have learnt only the basics with NONMEM; I have used WIN NONLIN in the >> past - recently I have added their WIN-NLME pop PK software to my >> subscriptions – should I use both NONMEM and NLME to run results ? would >> there be differences? I suspected that NLME may be easier for novice and >> students to catch up during short-student rotations to run simulations then >> to learn NONMEM on a 4 week rotation. Any opinions? >> > For simple popPK problems I don't think there is really much difference in > ease of use between NONMEM and Phoenix NLME. A NM-TRAN control stream is > probably simpler to learn how to write for this kind of very simple PK > problem rather than dealing with the layers of the Phoenix GUI. Phoenix > graphics are better than NONMEM but there are many ways to make graphs from > NONMEM using other tools such as Xpose. There won't be any important > differences in the results. > > If you have a NM-TRAN control stream or Phoenix NLME workflow set up then as > you add more data and want students on rotation to learn the basics of popPK > then running the model again is only a matter of seconds. The real time > required is learning the principles of PK models and population analysis and > how to interpret the results. Software run times are negligible compared with > that. > >> Thank you in advance for your help. >> >> Winnie >> >> Winnie Seto, BScPhm, PharmD, MSc, ACPR, R.Ph. >> >> Therapeutic Drug Monitoring Coordinator & Critical Care Unit Pharmacist >> >> Clinical Manager >> >> Department of Pharmacy >> >> The Hospital for Sick Children >> >> 555 University Avenue >> >> Toronto, Ontario >> >> Canada M5G 1X8 >> >> phone: 416-813-6236 >> >> fax: 416-813-5880 >> >> Confidentiality Notice: This is a medical communication. This e-mail >> message, including any attachments, is for the sole use of the intended >> recipient(s) and may contain privileged and confidential information. >> >> Any unauthorized review, use, copying, saving, re-transmission, disclosure >> or distribution is strictly prohibited. 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