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I am working on Pop PK data with intense sampling on day 1 and day 14 and trough conc in between and upto 240 days.
The half life of the drug is 50 hr and an autoinduction leads to increased Cl on day 14 (Literature).
I have a difficult time to calculate the Clearance since the intense sampling points didnt even last for half the half-life time. Please suggest me which structural model I have to try and how to calculate the Clearance and Vd on day 1 and day 14.
Thank you very much for your guidance.
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Hi Dr Lanlke, you certainly pose a very interesting question. I would like to present my initial proposal then others can elaborate on this proposal.
1) First you take intense blood sampling from 0 to 24 hours on Day 1 and evaluate Cmax, Tmax and AUC (0-24 hr). These are the only PK parameters you can determine precisely since you are dealing with a drug with such a long elimination half life.
2) You can then start multiple dosing (I presume the multiple dosing will be every 24 hours) and then do intense blood sampling on Day 12 (about 6 half lives). By that time steady state conditions would have been established for a drug with a t1/2 of 50 hours (by the way, this is not exceptionally long t1/2 since a widely used drug digoxin has a t1/2 of about 40 hours). You should also take trough levels on Days 11,10,9 and 8 to make sure that steady state conditions were established by Day 12.
3) On Day 12 you can obtain intense blood sampling for one dose interval (ie, 0-24 hr) and obtain all the steady state PK parameters such as Ctrough, Cmax(ss), Fluctuation Index =(Cm ax(SS) - Cmin(ss)/Cbar, Ctau, CL/F = daily dose/AUC (0-24), Accumulation index (R) = AC(0-24)ss/AUC(0-24)single dose (sd). From accumulation index R, you may be able to derive accumulation t1/2 and/or effective t1/2.
4) So, you cat establish number of critical PK parameters from intense blood sampling using the above study design. You may not even have to do population PK but should you desire to do so then you can obtain sparse sampling on rest of the 240 days. However, I don't know how you will be able to determine which structural model to use for your population PK evaluation. May be others can comment on this.
Regards Aziz Karim
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Since you mention "POP PK", I am assuming you are doing some sort of modeling of your data. However, I am confused by your statement that you are trying to estimate the clearance (which according to you changes over time due to autoinduction). Obviously, if you are modeling the data, you need to take into account that clearance is changing over time. One way would be for you to estimate clearance values for each day, using that day's data. This is not advised since there is really no use of such models. Knowing the value on day 1 or 14 does not help you estimate drug concentrations on day 10 or 100. A better way would be to incorporate the induction into the model in a way that induction kinetics can be estimated and hence the model can be used to simulate any time point.
There are several models published that incorporate the enzyme induction phenomenon but for some reason I like the following model most :-) :
- Gordi T. et al. Br J Clin Pharmacol. 2005 February;59(2):189-98 (saliva sampling)
- Asimus S, Gordi T. Br J Clin Pharmacol. 2007 June;63(6):758-62 (plasma sampling)
I believe you can download both articles for free from the Journal's website. Let me know if you need the model coding (for Nonmem).
Toufigh Gordi, PhD
President, PK/PD and Clinical Pharmacology Services
Rosa & Co. LLC (www.rosaandco.com)
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The following message was posted to: PharmPK Dear Shankar,
> I am working on Pop PK data with intense sampling on day 1 and day 14 and trough conc in between and > upto 240 days. The half life of the drug is 50 hr and an autoinduction leads to increased Cl on day 14
> (Literature). I have a difficult time to calculate the Clearance since the intense sampling points
> didnt even last for half the > half-life time. Please suggest me which structural model I have to try
> and how to calculate the Clearance and Vd on day 1 and day 14.
With 2 full profiles and trough concentrations during the induction and throughout the study, it is a very rich data to build the model. The physiological way to incorporate induction of clearance would be to add an enzyme turnover to the compartmental model of the drug and use an indirect-response model to represent the influence of drug on the enzyme and of enzyme on drug clearance. That is, the enzyme is being produced with zero-order rate and is being eliminated with the first order rate. It is in a steady state before the drug is given (you can set an arbitrary amount of enzyme in the enzyme compartment at time=0, say =1, since you do not measure the enzyme). The rate of enzyme production is increased with drug concentration (say as Emax model), and clearance of the drug increases with increase of the amount of enzyme in enzyme compartment. If the data allow (or require), you may add a delay of the enzyme increase by adding transit compartment(s). The following paper describes the model in
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