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Dear all,
I want to share my problem regarding plasma drug profile of soft
steroids given by inhalation route in animals. On inhalation
administration, it shows variable drug plasma concentration in
different animals of the same species. Even Cmax, Tmax, Vd, Kel and T1/2
also varies from animal to animal in the same species.
What may be the probable reasons for dissimilar plasma drug
concentration profiles?
Regards,
Dr. Nimesh
[Are your variations in Vd, kel and t(1/2) similar to what others report after
iv or po administration? Vd will be Vd/F and could vary with F. This could
cause differences in kel and t1/2.
What sort of formulation are you using. Particle size variation? - db]
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Other thoughts: drug delivered to different reigons of the respiratory tract
with differences in amounts absorbed. Or different amounts delivered to lung
different amounts "swallowed" and absorbed via GI tract.
Dave B
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Dear Nimesh,
can you be a little bit more specific, i.e. /which/ steroid? Can you
provide us with more details (CVs and ranges of the PK metrics)?
Remember that you are comparing different animals (inter-"subject"
variability). High variability is not uncommon in the inhalation route.
Best regards,
Helmut
--
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
web http://bebac.at/
forum http://forum.bebac.at/
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Hi Nimesh,
What animals were these drugs administered in? What was the device? (I
am
guessing a nebulizer).
Thanks,
Ray
Siladitya Ray Chaudhuri, PhD
Senior Scientist II
Simulation Technologies (GastroPlus)
Simulations Plus, Inc.
42505 10th Street W.
Lancaster, CA 93534, USA
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Nimesh,
As pointed by others, you can expect high variation in inhalation
administration. What are the variations reported for similar class of
compounds administered by inhalation route? This should give you a fair
idea of whether your variation is in acceptable range or not.
Regards,
Vinayak Nadiger
Vinayak Nadiger
Senior Scientist
Forma Therapeutics(Singapore)
11,Biopolis Way ,Helios # 08-05
Singapore 1386607
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Dear Nimesh,
In inhalation route the such variations are possible may be due to
amount of drug delivered by the instrument and also may be due to the
variatiopn in the physiology of the animals
Dr zafar
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In many such studies because of these variations, pharmackodynamics is
studied instead of pharmacokinetics
--
Thanks and regards
Anadi Chaturvedi
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Dear All:
About variation in PK/PD behavior. It seems to me that it simply is
what it is. How are we, as if we were God, going to decide what is
"acceptable"? The only thing I can think of is to use good population
PK/PD modeling strategies (exact likelihood methods, not constrained by any
parametric assumptions about the shape of the distributions, to get the
best models, and then too use multiple model dosage design to find the dosage
regimen that minimizes the expected weighted squared error in the
achievement of the target goal, whether it is a serum concentration or an
effect.
References:
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.
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.
3. 93. Jelliffe R, Bayard D, Milman M, Van Guilder M, and
Schumitzky A: Achieving Target Goals most Precisely using Nonparametric
Compartmental Models and "Multiple Model" Design of Dosage Regimens.
Therap. Drug Monit. 22: 346-353, 2000.
4. Jelliffe R, Schumitzky A, Bayard D, Leary R, Botnen A, Van
Guilder M, Bustad A, and Neely M: Human Genetic variation, Population
Pharmacokinetic - Dynamic Models, Bayesian feedback control, and
Maximally precise Individualized drug dosage regimens. Current Pharmacogenomics
and Personalized Medicine, 7: 249-262, 2009.
Very best regards for the New Year,
Roger W. Jelliffe, M.D., F.C.P.
Professor of Medicine,
Co-Director, Laboratory of Applied Pharmacokinetics
www.lapk.org
USC Keck School of Medicine
2250 Alcazar St, Room 134-B
Los Angeles CA 90033
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