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Hello Forum,
David's point about the usefulness of Clearance makes me wonder if
mean CL, which is what I think we've been discussing, could be
expanded to the range and calculation of probability of an individual
patient's position within the distribution. It would help to raise
awareness of lack of effect in fast clearers and overdose symptoms in
slow cases.
My impression is that more assay data is available than ever before so
perhaps the possibility of doing this is increasing. For example, the
adverse event reporting system has grown enormously in the last few
years, which might offer an opportunity to link slow CL with overdose
symptoms via assays done at the time of events. Perhaps if there were
a sensible scientific goal like this people would be more inclined to
take the blood samples in the first place. Also, clinical trials on
any one compound are more numerous and more fully reported than ever
before so I would expect that the typical regulatory database is also
increasing.
Andrew Sutton
[Isn't this one aspect of pharmacogenomics - db]
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The following message was posted to: PharmPK
andrew sutton wrote:
> David's point about the usefulness of Clearance makes me wonder if
> mean CL, which is what I think we've been discussing, could be
> expanded to the range and calculation of probability of an individual
> patient's position within the distribution.
In another part of the pharmacokinetic universe the discipline of population pharmacokinetics has been describing the distribution of individual clearances in the population for decades (e.g. Sheiner et al. 1972). More generally this is called the population approach.
Population PK typically assumes CL is distributed with an asymmetrical distribution e.g. lognormal because CL less than zero is not possible. The measure of central tendency of the population clearance is therefore most commonly reported as the geometric mean or the median.
From a population perspective one can think of the median clearance in everyone, CLpop, then in a defined group of individuals e.g. women, their is a median CLgroup, and finally in an individual CL there is the most probable value. The most probable value of clearance for an individual can be derived using a Bayesian approach given CLgroup, measured concs (zeor or more samples) and the variability in clearance and measurement error (see Sheiner et al. 1979).
Sheiner (personal communication) advised not to use the range as a description of variability because it is defined by two extreme individuals and ignores all the others in the population. A more robust measure is defined by an interval (e.g. 90%) enclosing a certain percentage of the population.
> [Isn't this one aspect of pharmacogenomics - db]
>
Pharmacogenetics (not pharmacogenomics according to my interpretation of
the ICH-E15 guidance) does indeed try to explain some part of variability in clearance by using DNA based genotyping. It typically explains only a small part of overall variability (eg. 30%) of clearance in the population.
Nick
1. Sheiner LB, Rosenberg B, Melmon KL. Modelling of individual pharmacokinetics for computer-aided drug dosage. Comput Biomed Res 1972;
5: 441-59.
2. Sheiner LB, Beal S, Rosenberg B, Marathe VV. Forecasting individual pharmacokinetics. Clin Pharmacol Ther 1979; 26: 294-305.
3. ICH. DEFINITIONS FOR GENOMIC BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC DATA AND SAMPLE CODING CATEGORIES E15
http://www.ich.org/LOB/media/MEDIA3383.pdf
2007; Step 4.
[from ref 3.
2.2.1.1 Pharmacogenomics: Pharmacogenomics (PGx) is defined as: The study of variations of DNA and RNA characteristics as related to drug response.
2.2.1.2 Pharmacogenetics: Pharmacogenetics (PGt) is a subset of pharmacogenomics (PGx) and is defined as: The study of variations in DNA sequence as related to drug response.
2.2.2 Additional Information
3. Drug response includes the processes of drug absorption and disposition (e.g., pharmacokinetics, (PK)), and drug effects (e.g., pharmacodynamics (PD), drug efficacy and adverse effects of drugs).
- db]
-- Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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