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Hello all,
I have question which is,
I want to fit the PCT profile of a drug X which follows linear kinetics with first order absorption
and elimination, 400 mg at 0,12,24 hrs, to 2 compartment oral model .Now my question is that since
i dont have any idea about the inital estimates to be supplied, can i use the PCT data from 0 hr to
12 hr post dose (ie concentartions obtained after 1 dosing ) for performing the Curvestripping and
use those estimates for my model fitting (since i have read from literature that rate constants,
volume of distribution of drug doesnt change much with dosing)
Regards
Kaushik
--
K.Harish Kaushik
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Dear Kaushik,
Do you have prior information to help with initial estimates? If you only have data at 0, 12, and 24
hours I fear you will be unable to garner anything useful as you will run into significant parameter
identifiability issues.
Given no information about absorption rate, where the inflection point is in the biphasic
disposition relevant to a two-compartment model, etc, there will likely be a substantial number of
mathematical solutions that may have little to no physiological validity.
In addition, I don't think curve stripping will do anything for you as you do not seem to have any
sampling times to distinguish the various phases.
Your "only" option that I forsee is if you have richer data from prior trials/other experiments to
provide guidance to the structural model and (initial) estimates.
Best of luck,
Devin Pastoor
Clinical research scientist
Center for Translational Medicine
University of Maryland, Baltimore
www.ctm.umaryland.edu
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Dear Dr. Kaushik:
There are much more capable methods for PK analysis than curve stripping. Population PK methods
are regarded as the best tools for this now, and nonparametric methods make fewer assumptions than
parametric ones. You might look at
1. Bustad A, Terziivanov D, Leary R, Port R, Schumitzky A, and Jelliffe R: Parametric and
Nonparametric Population Methods: Their Comparative Performance in Analysing a Clinical Data Set and
Two Monte Carlo Simulation Studies. Clin. Pharmacokinet., 45: 365-383, 2006.
Also, use of nonparametric pop models permits development of maximally precise dosage regimens
using the method of multiple model dosage design.
2. Jelliffe R, Schumitzky A, Bayard D, Milman M, Van Guilder M, Wang X, Jiang F, Barbaut X, and
Maire P: Model-Based, Goal-Oriented, Individualized Drug Therapy: Linkage of Population Modeling,
New "Multiple Model" Dosage Design, Bayesian Feedback, and Individualized Target Goals. Clin.
Pharmacokinet. 34: 57-77, 1998.
If you use only parametric models you will never be able to evaluate and optimize the precision
with which a dosage regimen hits its selected target goal.
You can get the nonparametric modeling software from the USC Lab of Applied Pharmacokinetics at
www.lapk.org.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D., F.C.P., F.A.A.P.S.
Professor of Medicine Emeritus
Founder and Director Emeritus, Laboratory of Applied Pharmacokinetics
www.lapk.org
USC Keck School of Medicine
Children's Hospital of Los Angeles
MC#51
4650 Sunset Blvd
Los Angeles CA 90027
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