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What parameter(s) identifies the latency to effective dose and the dwell (I am a machinist at heart)
at effective dose associated with protection offered by a drug
Ed O'Connor
efoconnor.-a-.gmail.com
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Dear Ed:
A good question! Most conventional PK models have a rate constant for oral uptake from the gut,
distribution into an apparent volume of distribution from which serum concentrations are measured,
and an elimination rate constant after that. There may also be a peripheral or non serum
compartment into which the drug is also distributed, with rate constants out to it and back from it.
Absorption begins instantaneously after the pill is popped into the mouth.
However, one may also put in a lag time during which nothing happens after taking the pill, and
things only start after this lag time. This may also be modeled as a series of compartments through
which the drug must pass before it reaches the venous or blood compartment.
As to dwell (duration of action?), that depends on the relationship between serum concentration
and effect. Often this has a Michaelis-Menten or a Hill model to describe this. However, there is
nothing equivalent to an on or off time. However, the greater the Hill coefficient, the steeper the
slope of the onset or offset of effect. Does this help? It also takes time for a cam to open a valve
on an engine or to close it.
All the best,
Roger
Roger W. Jelliffe, M.D., F.C.P., F.A.A.P.S.
Professor of Medicine,
Founder and Co-Director, Laboratory of Applied Pharmacokinetics
www.lapk.org
USC Keck School of Medicine
2250 Alcazar St, Room 134-B
Los Angeles CA 90033
email = jelliffe.aaa.usc.edu
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Ed,
On 27/08/2013 3:20 a.m., Ed O'Connor wrote:
> What parameter(s) identifies the latency to effective dose and the dwell (I am a machinist at
> heart) at effective dose associated > with protection offered by a drug
>Ed O'Connor
>
I struggled to understand what your question might mean (I am not a machinist).
Perhaps you are asking about what determines the time course of drug effect and how this is related
to the doses that are given?
This is the domain of pharmacokinetics and pharmacodynamics (PKPD). There are lots of educational
resources available in the literature and on the internet if you search for PKPD.
You might want to take a look at the introductory lecture slides here:
http://holford.fmhs.auckland.ac.nz/teaching/pharmacometrics/advanced.php
e.g. "Immediate time course of drug effect" and "Delayed time course of drug effect".
The basic ideas can also be found in this review written over 30 years ago but the principles have
not changed.
Holford NH, Sheiner LB. Understanding the dose-effect relationship: clinical application of
pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet. 1981;6(6):429-53.
The short answer to your question is that the primary parameters determining the time course of drug
effect are clearance (CL), volume of distribution (V), efficacy (Emax) and potency (C50). More
complex PK and PD models require more parameters.
The very special drug effect case of 'protection' depends on what you mean by this word. Protection
from smallpox by vaccination (very effective vaccines exist)? Protection from degeneration of
neurons underlying Alzheimer's disease (nothing exists for humans)?
Best wishes,
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
email: n.holford.-at-.auckland.ac.nz
http://holford.fmhs.auckland.ac.nz/
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Seems to me that the indirect response models approach developed by Jusko's group in Buffalo might
apply here. Lots of papers and examples available in the peer-reviewed literature as a guidance.
Dr. Daniel S. Sitar
Editor in Chief, Journal of Clinical Pharmacology
Professor Emeritus
Dept of Internal Medicine (Clinical Pharmacology)
Dept of Pharmacology and Therapeutics
Tel: 204-789-3532; FAX 204-789-3932
Web Address: www.umanitoba.ca/faculties/medicine/units/pharmacology
Email: sitar.-at-.cc.umanitoba.ca
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