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Is anyone aware of any literature supporting the use of either Clast vs
Cpred in the calculation of noncompartmental parameters? Is one
superior to the other and are there data to back up the choice?
thanks
--
Peter Bonate, PhD, FCP
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The following message was posted to: PharmPK
Dear Peter!
> Is anyone aware of any literature supporting the use of either Clast vs
> Cpred in the calculation of noncompartmental parameters? Is one
> superior to the other and are there data to back up the choice?
At least in Europe many people use Cpred instead of Clast in the
extrapolation of AUCinf. Otherwise we base the estimated value on a
single data point which we know to have the highest inaccuracy and
lowest precision of the entire profile (close to the LLOQ). Both methods
are available in standard NCA software (Phoenix/WinNonlin, Kinetica). I
didn't receive a single deficiency letter in my 500+ BE studies applying
this method - although I never went to the FDA. ;-).
Sauter R, Steinijans VW, Diletti E, BAPhm E and H-U Schulz
Presentation of results from bioequivalence studies
Int J Clin Pharm Ther Toxicol 30/Suppl1, S7-S30 (1992)
Hauschke D, Steinijans V and I Pigeot
Bioequivalence Studies in Drug Development
Chapter 6: Presentation of bioequivalence studies
John Wiley, Chichester, pp 123-155 (2007)
I don't know any reference comparing the performance of AUCobs
(Clast/lambda-z) with AUCpred (Cpred/lambda-z) in terms of bias and
precision. Hints are welcome.
When you are talking about a direct comparison of Clast/pred of two
formulations (e.g. Cmin in steady state) you are opening a can of worms.
Cmin,ss is a required metric of MR formulations in Europe. EMA in a
commentary document to the current BE guideline defined Cmin in steady
state as "By Cmin,ss we mean the concentration at the end of the dosage
interval, i.e. Ctrough"... Note that this is not the global Cmin
(minimum within the dosage interval). I'm not a native speaker of
English but "trough" in my understanding denotes a minimum (and not a
value at a particular time point). Of course in true steady state (no
lag-time assumed) we expect 50% of values to occur at t=0 and 50% at
t=tau. What if we have deviations from sampling scheduled at t=tau? Or -
even worse - missing values? 'Apples-and-oranges-statistics'
approaching. EMA requires predose samples taken at <=5 minutes prior to
administration and samples at tau A+/-10 minutes. In my steady state
studies I use the predicted Cmin at tau according to:
Cmin-pred=Clast*exp[-lambda-z*(tau-tlast)]
If sampling was performed at exactly t=tau, Cmin-pred=Clast since
(tau-tlast)=0 and exp(0)=1.
Gabrielsson J and D Weiner
Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications
Swedish Pharmaceutical Press, Stockholm, p163 (4th ed. 2006)
Best regards,
Helmut
--
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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The discussion of Cmin at steady state is very interesting. This is the reason why I tried
to introduce in Pharmacotherapy three parameters for Cmin at steady state. These are:
1. Cmin(0) = Cmin value before administration of the first dosr of thr drug usually in the
morning. Also sometimes referred to as predose Cmin.
2. Cmin(tau) = Cmin value at the end of dose interval. For BID dosing, it will be the
conc. at 12 hours and for QD dosing it will be the conc. at 24 hours.
3. Cmin(abs) = Cmin absolute is the lowest conc during the dose interval. This value can
occur at any time during the dosing interval.
For drugs with slow and continuous absorption or drugs that have circadian rhythm in PK or
drug formulations that have substantial food effects, the above three Cmin values can vary
widely.
My initial proposal did not get anywhere. I am happy that this topic is revived again. We
need to clearly define Cmin values in steady state studiers.
Aziz Karim, PhD, ABCP, FCP
AzK Consulting Inc.
Azia_karim.-a-.yajoo.com
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The discussion of Cmin at steady state is very interesting. This is the reason why I tried
to introduce in Pharmacotherapy three parameters for Cmin at steady state. These are:
1. Cmin(0) = Cmin value before administration of the first dosr of thr drug usually in the
morning. Also sometimes referred to as predose Cmin.
2. Cmin(tau) = Cmin value at the end of dose interval. For BID dosing, it will be the
conc. at 12 hours and for QD dosing it will be the conc. at 24 hours.
3. Cmin(abs) = Cmin absolute is the lowest conc during the dose interval. This value can
occur at any time during the dosing interval.
For drugs with slow and continuous absorption or drugs that have circadian rhythm in PK or
drug formulations that have substantial food effects, the above three Cmin values can vary
widely.
My initial proposal did not get anywhere. I am happy that this topic is revived again. We
need to clearly define Cmin values in steady state studiers.
Aziz Karim, PhD, ABCP, FCP
AzK Consulting Inc.
Azia_karim.at.yajoo.com
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I forgot to add a note on Clast(obs) vs. Clast(pred).
If you eliminate any extrapolated AUC that are greater than 30% (or even smaller, eg. 20%)
of the AUC (0-t) in deriving AUC (0-inf) values in assessing bioequivalence based on AuC
(0-inf) than use of either Clas(obs) or Clast(pred) becomes less critical.
In any case use of extrapolated AUC greater than 30% of AUC (0-t) in deriving AUC (0-inf)
will result in highly inaccurate estimate of AUC (0-inf) and should not be used as a PK
parameter. This often happens with long half-lives.
Aziz Karim, PhD, ABCP, FCP
AzK Consulting Inc.
Azia_karim.aaa.yahoo.com
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To Helmut:
"At least in Europe many people use Cpred instead of Clast in the
extrapolation of AUCinf. Otherwise we base the estimated value on a
single data point which we know to have the highest inaccuracy and
lowest precision of the entire profile (close to the LLOQ). "
It seems to me that for the estimation of the lowest observed plasma
concentrations {including the last time point} with a measurable plasma
concentration of a PK profile the use of weighted regression techniques
is very common nowadays. So may it depend on the assay validation work
for the specific drug whether the low points are indeed estimated with
the highest inaccuracy and lowest precision?. In cases where the
weighted regression was used could it be the case that the higher
concentrations have more inaccuracy or imprecision?
Regarding Peter's original question: I know of no information
rationalizing a preference of using C last (observed) or C last
{predicted} for the extrapolation of the terminal elimination phase to
get AUC inf. It seems to me it is basic point of fundamental judgement
or philosophy. I know that what I have done (for FDA) is to use the
observed concentration for Clast. Yet I emphasize that I used weighted
regression techniques for assay validation down to very low
concentrations prior to implementing a PK study.
Hope above remarks help,
Angus McLean
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