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Dear all,
We receive a query from a pharmaceutical company in Saudi Arabia. They
are planning conduct BE study with an extended release formulation it
follows non-linear pharmacokinetics. Whether steady state study required
for Saudi Arabia submission for this molecule.?
Narasimha Reddy
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Dear Mr Narasimha Reddy,
For Saudi Arabia submission, even if the extended release formulation
shows non-linear pharmacokinetics, there is no need to conduct Steady
state study for extended release formulation.
Because, single-dose studies are considered more sensitive in addressing
the primary question of bioequivalence (i.e., the release of the drug
substance from the drug product into the systemic circulation),
multiple-dose studies are generally not recommended, even in instances
where nonlinear kinetics are present.
Reference: Bioequivalence Requirements, Guidelines of Kingdom of Saudi
Arabia, Saudi Food and Drug Authority Drug Sector.
Regards,
Dr.S.Gunasakaran, MD
Head - Clinical Research & Medical Affairs,
Azidus, Clinical Research Organization, India
Global Moderator - ClinicalResearchForum
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The following message was posted to: PharmPK
I am not aware of the regulations in Saudi Arabia, but on scientific
principles, if a drug undergoes non-linear pharmacokinetics then a
steady
state study is essential.
For such drugs you will not be able to predict steady state exposure
from a single dose data.
You could always combine the single and multiple dose studies in one
study. Such a study design will provide you with many useful PK
parameters.
Regards.
Aziz Karim
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The following message was posted to: PharmPK
Aziz wrote:
> but on scientific
> principles, if a drug undergoes non-linear pharmacokinetics then a
> steady
> state study is essential.
> >
> For such drugs you will not be able to predict steady state exposure
> from a single dose data.
>
This conclusion is wrong. Models for non-linear pharmacokinetics can be
developed from single dose data and used to predict steady state
exposure.
Without such a model it is quite hard to predict what fraction of steady
state has been reached in any real life multiple dose study. So the idea
of doing a steady state study without using single dose data for the
design is not a scientific approach.
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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[Some of this thread was off list. I think I've got it back in order. Apologies to Nick and Aziz if I got it a little muddled. Please read from bottom up. - db]
Aziz,
I agree with you that a confirmatory multiple dose study is needed to evaluate drugs showing non-linear kinetics after a single dose. But you
need to do the single dose study and analyse it first before jumping into the multiple dose study (see Guentert et al 1994 for an informative
example).
Nick
Guentert TW, Holford NH, Pfefen JP, Dingemanse J 1994. Mixed linear and
non-linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B. Br J Clin Pharmacol 37(6):545-551.
--
Nick,
Please note that I am proposing confirmatory multiple dose study only for drugs that exhibit complex non-linear kinetics. For drugs that undergo simple linear kinetics, a single dose study would be more than adequate.
Aziz
--
Aziz,
Models for single dose kinetics drugs showing mixed-order elimination are plentiful in the literature (e.g. Holford 1987 and 1997). Why do you
insist that multiple doses are required?
Nick
1. Holford NH 1997. Complex PK/PD models--an alcoholic experience. Int J Clin Pharmacol Ther 35(10):465-468.
2. Holford NH 1987. Clinical pharmacokinetics of ethanol. Clin Pharmacokinet 13(5):273-292.
--
Aziz,
Multiple doses studies are just confirmation of something that single doses can predict. Multiple dose studies are empirical and costly, single dose studies are simple and science based.
Nick
--
Nick,
Multiple dose study will confirm that the non-linear PK model derived from the single doses data accurately predicted the systemic exposure at
steady state.
Just my opinion.
Aziz
--
Aziz,
Models for single dose kinetics drugs showing mixed-order elimination are plentiful in the literature (e.g. Holford 1987 and 1997). Why do you
insist that multiple doses are required?
Nick
1. Holford NH 1997. Complex PK/PD models--an alcoholic experience. Int J Clin Pharmacol Ther 35(10):465-468.
2. Holford NH 1987. Clinical pharmacokinetics of ethanol. Clin Pharmacokinet 13(5):273-292.
--
Thanks Nick,
I don't see how you can determine existence of non-linear kinetics based
on one single dose study. I am sure you will need to evaluate single dose PK characteristics at several dose levels to determine existence of
non-linear kinetics. =46rom these data you could then build a model to predict steady state systemic exposure of the drug based on single dose
non-linear kinetic model. Am I missing some thing?
With regards and best wishes.
Aziz
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The following message was posted to: PharmPK
Nick,
I completely agree with you. I never do a multiple dose study without
understanding drug's single dose characteristics in the fed and fasting
states.
Early food effect study is needed in order to know the best dosing
conditions to be used in the multiple dose study.
With my best wishes and regards.
PS. By the way I have now retired after 45 years in drug development.
Aziz
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