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The following message was posted to: PharmPK
Dear All,
Regarding the first time in man my experience is that you can not
extrapolate to human in a general manner. What you should do is carry out a
specific approach depending on the concrete behaviour of your drug in the
preclinical species and in vitro data and PK/PD modelling can help you in
doing this.
In my opinion, the safe starting dose in humans based upon body surface area
approach gives you a no efficacious dose. The dose that you obtain is a
conservative dose and it is usually used to assess the pk behaviour in
humans.
Regards,
Valvanera Vozmediano
DynaKin, S.L.
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Forum.
While I agree with Valvanera's comments I would add that you have to
try to reach suitable concentrations otherwise the first in man study
is a waste of time and that has negative ethical connotations as well
as commercial ones. As I have written here before it can be done in 6
gradual steps if safety is a particular concern by using the
two-group, three-doses-per-group design. That is also a useful guard
against poor absorption.
Andrew Sutton
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Dear Valvanera,
You are absolutely right and I am convinced by your suggestion. But you have to elaborate the things so that a beginner can also understand how to determine first in human dose & PK/PD modelling.
Regards,
Md. Tarique Imam
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In my opinion the optimum way to determine the FIH dose in a Phase I study
is to have conducted a human microdose study previously. By using
microdosing, a number of discovery candidate molecules can be evaluated for
human PK and the one with appropriate PK taken forward into Phase I. The
microdose PK parameters will provide a more certain starting dose for the
Phase I study without solely relying on animal model, PBPK and/or in vitro
data. Microdose PK appears to around 80% predictive of pharmacological dose
PK. I see microdosing as simply a continuum of FIH dosing being
particularly appropriate for molecules with unprecedented modes of action.
Professor Colin Garner BPharm PhD DSc FRCPath
Principal
Garner Consulting Services
Honorary Professor
Hull York Medical School
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The following message was posted to: PharmPK
Dear Tarique.
I'm very sorry for not make me understand well.
As I have told before each project is different even if you are working with
a new drug of a known family.
Regarding the pk/pd modelling what I usually do is to establish the pk/pd
modelling in the species in order to assess the behaviour in each one and
then compare between them. If the drug has a different behave between the
species I think that the best thing is look for the differences and once you
know where is the discrepancy try to find out the specie which is more
similar to human and use it as the relevant specie.
In order to extrapolate the pk parameters you can use the allometric
scaling. This method is based on the relationships between body weight and
the pk parameters. There are a lot of references regarding this approach.
This is an example of one of them:
A minireview of Iftekhar Mahmood : "Allometric issues in drug development"
Journal of Pharmaceutical Sciences
1999 Volume 88 Issue 11, Pages 1101 - 1106
http://www3.interscience.wiley.com/cgi-bin/fulltext/72505835/PDFSTART
Abstract
http://www3.interscience.wiley.com/journal/72505835/abstract
Moreover, you can establish relationships between physiological and pk
parameters. For example between the metabolic clearance and hepatic blood or
plasma flow (if you have information from blood or plasma drug
concentration, respectively) and then assess if this relationships are
maintained between the species.
On the other hand, regarding the pd parameters they are usually more similar
between species and you can use them as the parameters in humans. But, as in
the case of the pharmacokinetic you have to be very careful and try to
assess and integrate all the information you have.
Here you have one reference regarding the extrapolations of pk/pd
properties:
Clin Pharmacokinet 2007; 46 (5): 433-447
Animal-to-Human Extrapolation of the Pharmacokinetic and Pharmacodynamic
properties of Buprenorphine
Ashraf Yassen, Erik Olofsen, Jingmin Kan, Albert Dahan and Meindert Danhof
Best regards,
Valvanera Vozmediano
DynaKin, S.L.
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Dear Valvenera ,
I agree with your comments that the body surface area method gives a safe starting dose and not an efficacious dose.
Can you help me out in how to derive the human efficacious dose and also in projecting the MEC ?
Regards,
Raghav,
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Recent developments in the use of in vitro and pre-clinical data and PBPK
modelling have facilitated FIH predictions, please see the following papers
which might be useful:
Gibson CR, Bergman A, Lu P, Kesisoglou F, Denney WS and Mulrooney E (2009)
Prediction of Phase I single-dose pharmacokinetics using recombinant
cytochromes P450 and physiologically based modelling. Xenobiotica 39:637 -
648.
Lowe PJ, Hijazi Y, Luttringer O, Yin H, Sarangapani R and Howard D (2007) On
the anticipation of the human dose in first-in-man trials from preclinical
and prior clinical information in early drug development. Xenobiotica
37:1331-1354.
Jones HM, Parrott N, Jorga K and Lave T (2006) A novel strategy for
physiologically based predictions of human pharmacokinetics. Clin
Pharmacokinet 45:511-542.
Regards
Masoud
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The following message was posted to: PharmPK
Colin,
While I agree that microdosing is safe and the information useful for
repeat dose studies it has only a limited application to the classic
FIM, single dose regime as it does not really help in calculating the
dose. Before allometric scaling was developed I used to think about it
is as a pure clinical pharmacology project so to model the dose you
use the IV route, assume a typical blood compartment volume of 7
litres and if you have the target concentration the target dose is a
simple calculation. If the formulation is actually oral than you can
keep the same calculation or possibly adjust it upwards slightly. It
introduces a lot of variation in tmax as well as Cmax so I don't
regard the oral route as safe as IV. I would vary the proportion of
the target dose used for the very first dose level according to
potential safety issues around the mechanism of action. Then that
assumed target dose would be in the middle of 6 dose levels, one very
low starting dose for a guard against an immunological reaction but a
reserve of 1 or 2 higher doses as a guard against poor absorption. If
we reached target effect with unwanted side effects at a middle dose
the protocol was written to accommodate changing the higher dose
levels down to intermediate levels in order to detect the best effect
dose without adverse effects
Andrew
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Andrew,
Your approach looks very convincing. The statement "one very low starting dose for a guard against an immunological reaction" bothers me. Usually, this type of ADRs are classified as Type B, dose-independent.
Do you have some observation(s) that very low doses (how low) are safe and deprived of immunogenicity?
Kind regards,
Dimiter --
Dimiter Terziivanov, MD,PhD,DSc, Professor,
Pharmacology and Clinical Pharmacology,
Medical Faculty, University of Sofia "St. Kliment Ohridski",
1 Koziak str, 1407 Sofia, Bulgaria
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Dear Andrew,
I totally agree with your opinion regarding FIM dose estimation. Microdosing does help to understand safety of NCE's but cannot be used to determine FIM dose.
Regards
Md. Tarique Imam
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The following message was posted to: PharmPK
Colleagues
If I may make a few points of clarification about microdosing. In an
optimum microdosing study design both oral (if the proposed route of
administration) and intravenous administrations should be undertaken. As a
result of this design all the standard human PK parameters can be obtained
viz. AUC, t1/2, Cmax, V, F and CL etc for the investigated molecules. Armed
with this information, the FIH dose in the Phase 1 study can be calculated
on a human exposure basis perhaps taking a value such as 1/100th of the AUC
obtained from the microdose study. Once could also compare the human AUC
values with that obtained in animal models to ensure comparability of
exposure.
These approaches, together with IV PK protocols, are set out in the recently
published ICH M3 guidance document.
Colin Garner
Professor Colin Garner BPharm PhD DSc FRCPath
Principal
Garner Consulting Services
Honorary Professor
Hull York Medical School
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The following message was posted to: PharmPK
Thanks Dimiter for a good qurestion, as they say..
I agree that a pure anaphylactic reaction is independent of dose but I
still think it helps to minimise the dose when you are "in the dark"
and it really is the first time a human being has met the molecule.
But there are variants within the immune system like the Tegenero
effect, when a lower dose would have had a less severe effect. That
6-dose design does give you the luxury of a very low lowest dose and
that contributes to the feeling of safety even if it's not entirely
logical.
Does that answer the question?
Andrew
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Andrew, thanks for the detailed explanation.
I do agree that the Tegenero case was very instructive and revealed how relative is our knowledge when extrapolating data from animals to humans especially when dealing with such complex systems as immune system and biochemical interrelated pathways.
Have a nice weekend,
Dimiter
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