With flip-flop, we always can get 2 solutions (assuming 1-cmpt model
with absorption; 2-cpt case is similar but expressions may differ):
ka1-CL-V1 and ka2-CL-V2 such that
ka1=CL/V2 and ka2=CL/V1
Note that CL is the same, so info on CL will not help to distinguish
these cases.
One cannot just fix the volume, as it should have one of the values V1
or V2, but one can select the "more mechanistic" value if other
information (e.g., about similar compounds) is available, and push the
solution to the right place by providing the bounds on the range of
possible parameter estimates.
Note that with SC dose, we cannot estimate CL and V, we have apparent CL
and apparent V (related to the underlying CLtrue and Vtrue as
CL=CLtrue/F and V= Vtrue/F, where F is the absolute bioavailability of
SC administration). When apparent CL and apparent V are compared with
parameters for other compounds, F should be taken into account.
Thank you
Leonid
On 9/13/2022 10:54 AM, Bonate, Peter wrote:
In comment to Shan’s statement:
It's my understanding that this flip-flop phenomenon is fundamentally a
mathematical problem -- that is, if we write down a PK model in its
analytical form, it becomes rather easy to understand that swapping the
values between ka and ke (CL/V) would lead to the same output.
This is not true. The values do not swap out. V will be different.
Consider a 1-compartment model with KA=0.1 per h, KEL=0.7 per h, and
V1=125L. Suppose a 250 mg dose is given. This model has flip-flop
kinetics.
Now assume we build a model with KA=0.7 per h, KEL=0.1 per h, and V2 is
unknown, same dose. This model does not have flip-flop. Using the
simulated data from model 1 as the observed data for model 2, we can fit
model 2 and find the optimum value of V2. In this case it is 875L. If
you look at the profiles you will see that they are /exactly/ the same.
So it’s not a matter of just changing the order of the exponents.
If you want to estimate the parameters of a flip-flop model you need a
data without absorption – IV. Or some other independent assessment of
CL that does not depend on absorption.
*Peter Bonate, PhD*
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS)
Clinical Pharmacology and Exploratory Development (CPED)
Astellas
1 Astellas Way
Northbrook, IL 60062
peter.bon...@astellas.com <mailto:peter.bon...@astellas.com>
(224) 619-4901
Quote of the week –
/“Dancing with the Stars” is not owned by Astellas.**/
*From:* owner-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> *On
Behalf Of *Shan Pan
*Sent:* Tuesday, September 13, 2022 3:42 AM
*To:* Jakob Ribbing <jakob.ribb...@pharmetheus.com>; Niurys.CS
<amaranth...@gmail.com>
*Cc:* nmusers <nmusers@globomaxnm.com>
*Subject:* Re: [NMusers] flip-flop without absorption information?
This is an interesting discussion. At the same time I can't get my head
around the assumption of any covariate on a flip-flop phenomenon. In
other words, even if there is no information on covariates
this phenomenon could still exist.
It's my understanding that this flip-flop phenomenon is fundamentally a
mathematical problem -- that is, if we write down a PK model in its
analytical form, it becomes rather easy to understand that swapping the
values between ka and ke (CL/V) would lead to the same output.
In the absence of data on drug absorption as in your case, I think the
solution could lie in fixing volume of distribution based on any prior
information, e.g. a reported value in the literature. Otherwise, try to
fix it to a reasonable estimate and see what happens.
Hope it helps.
Kind regards,
Shan
On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing
<jakob.ribb...@pharmetheus.com <mailto:jakob.ribb...@pharmetheus.com>>
wrote:
Dear Niurys,
It would be down to distributional assumptions in that case.
For example if you have a very strong predictor (covariate) of
either elimination or absorption rate (but not both) - data could be
informative to discriminate between flip-flop or not.
Had your therapeutic been IgG monoclonal antibody, albumin wold have
been a predictor of the absolute CL that with a larger number of
subjects may allow to discriminate (especially if a mix of both
healthy, and patients with higher inflammation level and thereby
lower albumin -> higher CL).
On the other hand, for example body weight would not be helpful in
this regard.
Even if body weight would have an effect on CL and V, it would not
have a major impact on terminal elimination (and in addition one
could have a concern on body weight also affecting the absorption rate).
So you would need both the mechanistic knowledge on the covariate,
for your therapeutic peptide in the RA population, and it would need
to be a strong effect in sufficient number of subjects.
On such obvious covariate would be different routes of
administration, where nobody would question the mechanistic
knowledge on that SC has a slower absorption that IV :>)
In liu of IV dosing this becomes a more challenging task, however.
Best wishes
Jakob
On 13 Sep 2022, at 05:05, Niurys.CS <amaranth...@gmail.com
<mailto:amaranth...@gmail.com>> wrote:
Niurys
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