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Dear all,
I have one question regarding nonlinear pharmacokinetics.
In a dose promotional study i got a data indicating linear increase in AUC (as increase in dose 50, 100, 200, 400mg), but t1/2 varies significantly (2hrs, 3.5hrs, 5hrs, 7hrs respectively). I do not have clearance and Vd data right now. Protein binding is 45%.
So what to say?
Drug is following linear kinetics on dose proportional basis or
Drug is following non-linear kinetics on t1/2 basis?
In this data can anybody guess what should be the pattern of CL, Vd and kel?
Eagerly waiting for your comment.
Regards,
Rahul Vats
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Dear Rahul,
Your question would be best answered by modeling all the data together. Without it, the only thing you can say is that CL/F does not depend on dose. You could observe increasing half-life with the linear PK if the drug has multi-compartmental kinetics and "terminal half-lives" can't be seen at lower doses as they are below LOQ. Alternatively, you could have a flip-flop with absorption rate dependent on dose. Then the half-life calculated from the terminal slope would reflect half-life of absorption, not elimination and would not influence AUC.
Regards,
Katya
Ekaterina Gibiansky, Ph.D.
CEO&CSO, QuantPharm LLC
Web: www.quantpharm.com
Email: EGibiansky at quantpharm.com
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Hi, Could it be that at higher doses you are able to follow the profile longer and are estimating the thalf of a slower elimination phase at low concentrations? Regards, Frieda
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The following message was posted to: PharmPK
Dear Rahul,
It seems at higher doses you need to extend the sample collection time points to pick up the true elimination half life.
You can compare the last time point concentrations of low vs higher doses to get an idea.
This could be the reason for your t1/2 variations.
Hope it helps
Thanks & Regards
Raja Reddy Kallem
DMPK lab
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The following message was posted to: PharmPK
Hello Rahul,
I suggest you to look at your profiles and observe if there is any change in the no of exponents (1/2/3)?? In NCA, you will be calculating the terminal t1/2 based on your Lambda Z which is determined by your exponents. Moreover, as we all know, it requires a clearly defined terminal phase
Also look for any change in the disposition pattern with a change in the dose.
I also agree that modeling that data could give a better picture especially about half-lives.
Hope this could be helpful
Thanks
Ravi Talluri PhD
Sai Advantium Pharma, Pune
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The following message was posted to: PharmPK
Dear Rahul,
It would help a lot to know whether the increases in t1/2 were
observed following iv or oral administration of the compound.
Kind regards,
Sheila
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Dear all,
Thanks for your expert comment.
Regarding route of administration it was P.O. and also i would like to add some information regarding Vd which increases with increase in dose.
Regards,
Rahul Vats
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The following message was posted to: PharmPK
Dear Rahul,
The non-linear t 1/2 can be from 2 different sources:
1. a nonlinear volume of distribution
2. A dose-dependent drug induced impairment of gastric emptying.
It is possible to distinguish between the two, if you have dose dependent PK for at least 2 iv doses. If you observe similar t 1/2 increase with respect to dose in iv too, then it is coming from nonlinear Vd. If on the other hand, t 1/2 increase is seen only in oral, then it is due to the latter (a dose-dependent drug induced impairment of gastric emptying). A delayed gastric emptying can limit the absorption rate and extend the absorption phase leading to flip-flop kinetics.
As AUC is dose-linear, nonlinear t 1/2 cannot be from CL.
Regards,
Sheila Peters
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The following message was posted to: PharmPK
As a follow on from Sheila's comment about non-linear t1/2 being due
to a dose-dependent drug-induced impairment of gastric emptying, I
would just add that it does not have to be a pharmacological effect
because it may be caused by any drug that induces nausea.
Andrew Sutton
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Sheila wrote:
< The non-linear t 1/2 can be from 2 different sources:
1. a nonlinear volume of distribution
2. A dose-dependent drug induced impairment of gastric emptying.
It is possible to distinguish between the two, if you have dose dependent PK for at least 2 iv doses. If you observe similar t 1/2 increase with respect to dose in iv too, then it is coming from nonlinear Vd. If on the other hand, t 1/2 increase is seen only in oral, then it is due to the latter (a dose-dependent drug induced impairment of gastric emptying). A delayed gastric emptying can limit the absorption rate and extend the absorption phase leading to flip-flop kinetics.
As AUC is dose-linear, nonlinear t 1/2 cannot be from CL.>
Regarding "dose-dependent drug induced impairment of gastric emptying" I agree with Andrew's point that this is toxicological (type 'A' ADE) rather than pharmacological event.
As far I understand your expanations non-linear volume of distribution, as a source for PK non-linearity, can only be deduced from IV designed experiments. Am I correct in my understanding? Have a nice weekend,
Dimiter
--
Dimiter Terziivanov, MD,PhD,DSc, Professor
Univ Hosp "St. Ivan Rilski", 15 Acad. Ivan Geshov st, 1431 Sofia, Bulgaria
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Dear Sheila,
Thanks for your prompt reply.
As we pin pointed towards two reason for t1/2 change
1) Could be due to change in Vd
2) Could be due to change in gastric emptying.
Change in gastric emptying will show Tmax change,but i did not get it as Tmax is almost constant.
I observed dose dependent change in Vd,though it is not influencing AUC other than t1/2.
So can we say that it is following linear kinetics though change in Vd is nonlinear?
Regards,
Rahul Vats
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The following message was posted to: PharmPK
Dimiter and Sheila,
Nonlinear t 1/2 can be caused by more than just nonlinear volume of
distribution or gastric emptying. Saturable metabolism and saturable
transport (both in absorption and in a variety of tissues), as well as a
complex interaction between those two, can also contribute to nonlinearities
in PK, including t 1/2.
Absorption itself is always nonlinear - there is no such thing as a constant
ka - I believe it's safe to say that it varies significantly with time for
_every_ orally dosed drug, and likely so for anything other than vascular
administration. The fact that ka can sometimes be approximated as a constant
is, in my opinion, unfortunate, because it leads to the common misconception
that ka is actually constant. In fact, when fitting oral data with a
constant ka, PK parameters will be adjusted to compensate, so they are
"compromised". Perhaps not always enough to be significant, but nonetheless
if the absorption is modeled as time-variant to constant, (absorption = drug
entering the enterocytes in the gut), different PK parameters will be
obtained when fitting plasma concentration-time data.
The same goes for clearance - we can often approximate it as constant, but
Mother Nature doesn't know it's supposed to be constant, and I'll wager that
there is no such thing as truly constant clearance, even for one dose in one
subject on one occasion. On the other hand, it is quite often
well-approximated as a constant, so under the "some models are useful"
concept, it is useful (when it is appropriate).
Note also that gastric emptying can be dose-dependent without being an AE.
Certain drugs (exenatide, taspoglutide, etc.) cause delayed gastric
emptying, and coadministration of these with other drugs can affect the
absorption rate vs time (and sometimes the bioavailability) of the second
drug.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Rahul,
I disagree that the drug effect we are discussing would necessarily
change tmax. Particulalrly when it is a central effect it would only
come into play after the initial absorption phase and that is quite
likely to be too late to delay Cmax.
Andrew
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Walt,
Thanks for your note! I completely agree with you when pointing out that " Saturable metabolism and saturable
transport (both in absorption and in a variety of tissues), as well as a complex interaction between those two, can also contribute to nonlinearities
in PK, including t 1/2."
Just for endorsement: Years ago an attempt was undertaken to rationalize this phenomenon in improving BA of some medicines like levodopa(e.g., Woods AC. et al. Sustained-release of levodopa. Lancet 1973; 1(7816): 1391 and Sasahara K. et al. Dosage form design for improvement of bioavailability of levodopa III: Influence of dose on pharmacokinetic behavior of levodopa in dogs and Parkinsonian patients. J Pharm Sci. 1980; 69: 1374-1378).
The rationale was to find out a threshold dose saturating enough presystemic L-DOPA elimination. But, as far as I understood this particular case, as depicted by Rahul, there were no insights for such a behaviour. AUC was dose-linear. You wrote:
Yes, I do accept your statement. I mentioned 'AE' since Sheila indicated as a second source for non-linearity "A dose-dependent drug induced IMPAIRMENT of gastric emptying." My point is that if a given physiological function is impaired by a given medicine this event can be deemed as AE.
Kind regards,
Dimiter
--
Dimiter Terziivanov, MD,PhD,DSc, Professor,
Univ Hosp "St. Ivan Rilski", 15 Acad. Ivan Geshov st, 1431 Sofia, Bulgaria
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The following message was posted to: PharmPK
Hi Rahul,
According to me your question looks some what strange.
If your elimination half life is increasing with dose that means your AUC
should also increase non linearly.
Since elimination half life is increasing this shows that your drug is
present in the circulation and hence AUC should increase.
There are no. of reason for non linear increase in Elimination half life
1. Saturation in drug metabolism
2.Renal reabsorption
3.Enterohepatic recirculation
4.Colonic reabsorption
If this is not the case then there is something to do with absorption.
What about the Cmax,is it increasing dose proportionately or remaining
constant across doses?Do you have %F data for the drug?
regards
Anasuya
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The following message was posted to: PharmPK
Dear Rahul,
Although changes in tmax are likely to accompany gastric emptying delay,
I am not sure if that is a necessary condition. I would eliminate the
possibility of gastric emptying delay, by doing a dose dependent iv, if
this is feasible. If Vd is confirmed to be the source of nonlinearity,
the PK should still be described as nonlinear in my opinion, although
there is linearity with respect to CL.
Kind regards,
Sheila
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The following message was posted to: PharmPK
Dear Anasuya,
You wrote:
> If your elimination half life is increasing with dose that means
>your AUC should also increase non linearly.
This is not necessarily so. E.g., an increase in the volume of
distribution, or a change in the absorption rate resulting in a
'flip-flop', will result in a increased half-life without a change in
AUC.
Please note that the original message stated that AUC did not change.
Therefore the possibility of nonlinear elimination was correctly not
mentioned in that message (this was overlooked by other responders as
well).
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
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The following message was posted to: PharmPK
Hello Dr Proost,
I am not still satisfied with your reply towards my mail.
Consider Volume of distribution, if the drug has distributed in different
tissues then with time the drug will tend to redistribute back to systemic
circulation .
In this case the drug will be in the systemic circulation for greater
period of time. Inshort it may act as depot.I think that in this case also
the the AUC should increase.
Regards
Anasuya
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Dear Anasuya,
You are right. The drug will equilibrate with different rate with systemic circulation and may follow more than one compartment model. If the drug is deposited in highly fatty tissues. then it may stay for longer period of time.
Dr Zafar
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The following message was posted to: PharmPK
Dear Anasuya,
You wrote:
> Consider Volume of distribution, if the drug has distributed in different
> tissues then with time the drug will tend to redistribute back to systemic
> circulation .
> In this case the drug will be in the systemic circulation for greater
> period of time. Inshort it may act as depot.I think that in this case also
> the the AUC should increase.
In the case of distribution in different tissues, the plasma concentration
will be lower, and the AUC remains the same.
Please note that this way of reasoning is not the proof of the statement
that a change of V does not affect AUC. The latter follow from:
rate of elimination = CL * C
After integration from 0 to infinity it follows that:
total amount eliminated = CL * AUC = F * Dose
So, AUC depends on Dose, F, and CL, and not on V.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
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