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Re: The theory of relativity for CL and V...

From: Paolo Denti <paolo.denti>
Date: Mon, 07 Jan 2013 17:20:56 +0200

Dear Rob,
thanks for the suggestion.

While a well stirred model could indeed address the issue in a more
mechanistic way, the problem is that we would need estimates of hepatic
blood flow and the patients in the study are malnourished children, some
younger than 3 months of age. I am not sure how reliable the
weight-based formulas for blood flow are in such a population, but it
could be an option to explore.

The drug is isoniazid, and we don't have data on the metabolite, so the
choice of lower bioavailability, besides being plausible, is based
mostly on the NONMEM OFV.

Based on the current parametrisation and model, how would you report the

Thanks again,

On 2013/01/07 16:24, R.ter.Heine
> Dear Paolo,
> The reduced bioavailability is most likely a result of increased,
> however variable, pre-systemic metabolism which also correlates with
> systemic clearance. Have you tried linking these together in your model,
> e.g. with a well-stirred liver model (e.g. Gordi et al Br J Clin
> Pharmacol. 2005 Feb;59(2):189-98.)? This would most likely give you a
> more accurate estimation of (relative) bioavailability, and thus
> clearance and volume of distribution in comparison with a model with a
> BSV on CL/F and a separate BSV on F.
> Perhaps off-topic: What drug are you studying? Efavirenz? The
> CYP2B6-mediated metabolite 8-hydroxyefavirenz may be easily measured.
> You could investigate whether metabolite data support your hypothesis.
> Cheers,
> Rob
> ------
> R. ter Heine, PhD, PharmD
> Hospital pharmacist i.t.
> Meander Medical Center, Amersfoort, The Netherlands
> T: +31-33-8502335
> E: r.ter.heine
> -----Oorspronkelijk bericht-----
> Van: owner-nmusers
> Namens Paolo Denti
> Verzonden: maandag 7 januari 2013 14:19
> Aan: NMusers
> Onderwerp: [NMusers] The theory of relativity for CL and V...
> Dear NMusers,
> we have a question we have been debating in our group, we have come to
> an agreement, and we would like the input from the NMusers community. It
> is about how to report values for clearances and volumes when the
> relative bioavailability is fixed to values different from 1 in some of
> the subjects.
> We developed a 2 compartment POPK model for an orally administered drug
> that is a substrate of polymorphic enzyme. Individuals are categorized
> as slow, intermediate and fast metabolizers.
> Since no IV data were available, relative bioavailability was fixed to 1
> for slow metabolizers, and it was found to be 20% lower (and thus 0.8)
> in fast and intermediate metabolizers. On top of this difference in
> bioavailability, clearance was estimated to be 6, 11 and 14 L/h for
> slow, intermediate and fast metabolizers, respectively. The other
> clearances and volumes in the model (V, Q, V3) were the same in the
> three groups.
> Our question is on how to report clearances and volumes for each group
> of metabolizers.
> Since we only have oral data, we can only estimate oral clearance (e.g.
> CL/F), and normally this is what we would like to report, but in our
> case this means dividing the values of CL provided by NONMEM for the
> different metabolizers by their respective bioavailability. This would
> imply reporting 3 different values not only for CL/F, but also for V/F,
> Q/F and V3/F, resulting in a over-populated table.
> Moreover, since the model contains BSV both in CL and bioavailability,
> also the BSV of CL/F should be calculated if we want to report it.
> For these reasons, we decided it is best to report the "pure" values of
> CL, V, Q and V3 used in the NONMEM model, and then state that, to obtain
> CL/F, V/F, Q/F and V3/F, one should divide by the respective
> bioavailability. Does this make sense?
> If so, how would you indicate the parameters in the table? Calling it
> only CL gives the idea that we are providing the value of absolute CL,
> which is not possible without IV data. What we are indeed reporting are
> the values of CL (or V, Q, V3), if the bioavailability is fixed to a
> certain value (1 for slow metabolizers, and 0.8 for intermediate and
> fast). Is there a specific name that could be used for that? Would a
> simple explanation under the table be acceptable?
> What is the experience of the community with this? Any suggestions?
> Thank you in advance for your help,
> The pharmacometrics group at the University of Cape Town
> --
> ------------------------------------------------
> Paolo Denti, PhD
> Junior Lecturer
> Division of Clinical Pharmacology
> Department of Medicine
> University of Cape Town
> K45 Old Main Building
> Groote Schuur Hospital
> Observatory, Cape Town
> 7925 South Africa
> phone: +27 21 404 7719
> fax: +27 21 448 1989
> email: paolo.denti
> ------------------------------------------------
> ***************************DISCLAIMER****************************
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Paolo Denti, PhD
Junior Lecturer
Division of Clinical Pharmacology
Department of Medicine
University of Cape Town

K45 Old Main Building
Groote Schuur Hospital
Observatory, Cape Town
7925 South Africa
phone: +27 21 404 7719
fax: +27 21 448 1989
email: paolo.denti

Received on Mon Jan 07 2013 - 10:20:56 EST

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