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Dear all,
We are working on an intratracheal PK of a highly lipophilic compound in rat. Typically,
we administered the compound as a suspension and also as a DPI powder intratrachaelly
and collected systemic plasma, BAL fluid and whole lung tissues at different time points.
The concentration in each matrix was determined using LC-MS-MS. The max. conc. was
achieved in lung and bal fluid. The plasma conc. were negligible. However at any given
time point up to 48 h post dose, we could recover only 20% of the dose administered
combined in lung and BAL fluid collectively. I ruled out the possibility of lung
metabolism based on an in vitro lung microsomal stability experiment. I discussed the
possibility of mis-dosing with our Vet staff, but he ruled out that based on his
experience. The compound is poorly absorbed after oral administration.
I also came across a recent paper from Merck (European Journal of Pharmacology 643 (2010)
274-281) , wherein they have reported only 20% deposition (lung & BAL fluid) after
intra-tracheal administration of a PDE4 inhibitor. Is that pretty common with
intratracheal dosing like that of inhalation dosing?
I have also read about higher mucociliary clearance after intratracheal dosing as
compared to inhalation dosing of compounds in rabbits but nothing conclusive in rats. Can
this cleararance be so high that 80% of of drug administered is cleared without
deposition on lung? Is there any way (apart from imaging) to measure the mucociallry
clearance?
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Try a mass balance study with 14C labeled compound if possible
Stanley Cotler
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Dear Satya,
We have had the same experience during our course of drug discovery. In fact Intratracheal
instillation does not mimic the inhalation route, but there is no other choice than to
follow this route of administration during the discovery stage. Secondly, we did a tissue
distribution study (with cold compound), where lung was collected at serial time points
and the ratio of lung to plasma
Exposure was estimated, which indicated drug deposition in lungs(ratio > 1000 folds).
May be this would help you in assessing lung deposition.
Regards,
Dr Pradeep Sharma
Clinical Pharmacology and Pharmacokinetics.
Ranbaxy
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Dear Satya,
Dealing with intrapulmonary delivery studies one is facing several
problems
1. determination of cpd concentration in tissue/lung samples.
Measuring tissue concentrations quantitatively is very difficult since
extraction from tissue is often not quantitative.
Conducting a 14C mass balance study is likely the best way to show lung
deposition/retention quantitatively.
Cold results give an qualitative impression about the lung to plasma
split, which is normally high as long as solid material is present in
the lung.
2. The different methods (e.g. inhalation, instillation, insufflation),
routes (e.g. nasal vs. oral inhalation, intranasal vs. intratracheal
instillation) and technical/formulation issues (e.g. dry powder vs.
lactose blended aerosol, instillation technique) have major impact on
fraction and regional deposition and clearance.
A good instillation technique with suspension will results in
approximately 100% lung deposition and very low plasma concentration
variability, but
- material already dissolved in the suspension (assuming moderate
permeability) will quickly enter circulation
- incomplete deposition due to expiration of suspension following
instillation depending on instillation technique. You can control this
in an mass balance study: remove lungs, trachea and oesophagus+stomach
immediately after instillation and quantify total radioactivity
The publication below describes the dose calculation following
inhalation
Alexander et al., Association of Inhalation Toxicologists (AIT) Working
Party Recommendation
for Standard Delivered Dose Calculation and Expression in Non-Clinical
Aerosol Inhalation Toxicology Studies with Pharmaceuticals, Inhalation
Tox, 2008
3. Mucocilliary particle clearance from rat tracheal-bronchiolar region
is fast (rule of thumb ~95%/6h vs. human 24h)
Major clearance mechanism from the alveoli is dissolution (for slowly
soluble particles). An anorganic particle (e.g. an asbestos fibre) may
stay there a very long time)
It's not easy to compare instillation and inhalation, since there are
major differences, e.g.
- instillation: deposition of all particle sizes vs. inhalation:
particle size and shape determines regional deposition
--> via instillation you will deposit large particles (>6um) in the deep
lung compartment which will never be deposited in the lung via
inhalation and
--> those large particles show slow dissolution, because of small total
surface area. So instillation may pretend a very long retention which is
not the case following inhalation.
- also the regional deposition pattern is different and hence also the
fraction cleared via the mucociliary escalator is different.
To get an impression about deposition and clearance, impact of particle
distribution and so on it is very helpful to play around with the easy
to use MPPD (Multiple-Path Particle Dosimetry Model V 2.0) software
tool. It is free, you can get it here http://www.ciit.org/mppd/
or http://www.ciit.org/techtransfer/tt_technologies.asp
You will get a lot more in formation in the help section.
I hope this was helpful
Kind regards
Clemens
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Dear Clement, Satya and others,
MPPD is a good model/software for predicting the fraction of inhaled drug
deposited in each generation (region) of the lung. In fact, it is an
extension/improvement of the ICRP 66 deposition model, a first of this kind.
[ICRP Publication 66: Human Respiratory Tract Model for Radiological
Protection
Annals of the ICRP Volume 24/1-3
ISBN 10: 0-08-041154-1
ISBN 13: 978-0-08-041154-5]
However, it is yet to be determined or proven whether the increased level of
sophistication with the MPPD model results in a better prediction of in vivo
pulmonary bioabavailability, which is a complex interplay of (as Clement
mentioned) dissolution, mucociliary transit (and swallowing), absorption and
a few other factors. Moreover, according to Prof. Warren Finlay (who is
considered an authority in the area of predictive deposition modeling) all
of these models predict deposition from breathing in an open environment and
do not accurately represent administering the dose from a device. Warren
says
"At present, models for mouth-throat deposition exist only for unencumbered
inhalation of aerosols and are meant for modeling the fate of environmental
and occupational aerosols (ICRP 1994). These models are empirical and
provide equations that fit experimental data on in vivo mouth-throat
deposition in human subjects inhaling via straight tubes inserted into the
mouth. Such models can be expected to, accurately predict mouth-throat
deposition only for pharmaceutical inhalation devices that supply aerosol to
the mouth via a geometry that resembles that of a relatively long, straight
tube. Most pharmaceutical inhalation devices do not resemble straight tubes
in their fluid mechanics (the most notable exception being some nebulizer
designs, which do supply nearly a straight tube for inhalation), so that
existing mouth-throat deposition models are inappropriate for quantitative
prediction of mouth-throat deposition with many pharmaceutical inhalation
devices."
[quoted from The Mechanics of Inhaled Pharmaceutical Aerosols: An
Introduction by Warren H. Finlay, Pg 148
ISBN-10: 0122569717
ISBN-13: 978-0122569715]
We incorporated the ICRP 66 model (as a starting point) to model regional
deposition within the nasal-pulmonary module of GastroPlus in order to
predict its disposition (dissolution/absorption/PK) behavior across a
variety of solution and suspension dosage forms. ICRP 66 is also a part of
the software LUDEP.
Hope this helps.
Kind regards,
Ray
Siladitya Ray Chaudhuri
Senior Scientist, Simulation Technologies
Simulations Plus, Inc.
42505 10th Street W.
Lancaster, CA 93534, USA
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