Back to the Top
Hi all,
I have a question, what is the PK criterion to decide whether the compounds should be considered continuously or discard!?
For example, the compound have a very short half life or degraded very quickly in vivo, and after IP administration to mice the absorbtion rate is very low, however the drug effect is significant, should I discard the compounds or not?!
Thank you in advance.
Back to the Top
Dear Wang,
Its very difficult to decide on the basis of pharmacokinetic parameters only. All other factors sould be taken in to account.
1) Like, though this molecule is having short half life ,but effect may be long lasting (hit and run phenomenon of the molecule) So look at your PK/PD correlation.
2) There is no straight line correlation of a molecules clearence in mice and human i.e. there are many drug which shows high ] clearence in mice but very low clearence in human.
3) Do you have any backup molecule?
4) Is it first in class drug/molecule?
5) Whether this molecule is having some pharmacodynamic advantages e.g. Lesser toxicity as compare to existing drugs, higher potency etc.
Hope this will help
Regards,
Rahul Vats
Back to the Top
Hi Changguang,
I think only focusing on the PK properties of a compound can be quite misleading and may makeyou discard best in class drugs for wrong reasons. Don't misunderstand me, it is very important to know the time course of the drug concentrations in the body. This is important because once you have established the relation between drug concentrations and the desired (or undesired) effect, you may use various tools to estimate the best dose and dosing regimen for the compound. There are many examples of drug with short half-lives that are administered once or twice daily, resulting in optimal efficacy. In my opinion, it is rather premature to exclude a compound for further development based on, e.g., a short half-life in rats or low bioavailability in dogs. These properties may be of no significance in how the drug affects its target receptor and the extend and duration of the effect.
The best approach for you would be to model your PK and connect the drug concentrations to your effect (a PK/PD model). Once the model is in place, you can simulate various scenarios and find out whether a short half-life or slow rate of absorption needs to be addresses in further development of the compound.
Toufigh
Toufigh Gordi, PhD
President, PK/PD and Clinical Pharmacology Services
Rosa & Co. LLC (www.rosaandco.com)
Back to the Top
Hi Toufigh,
My understanding is, initial PK screening is used to rank order
compounds based on their PK characteristics. Compounds with good
plasma/tissue concentrations are chosen for further testing in the
cascade.
Consider this scenario: Compound X gets discarded based on PK selection
criteria. Compound X was tested for efficacy for other reasons and found
to be highly efficacious. Compound gets into development pipeline for
its merit of being efficacious.
How one would avoid a situation of missing such compounds?
Regards,
Vinayak Nadiger
Vinayak Nadiger
Manager, Bioanalytical
Forma Therapeutics(Singapore)
11,Biopolis Way ,Helios # 08-05
Singapore 1386607
Back to the Top
Hi Vinayak,
It is a very interesting question and I have actually been working on and off on a manuscript on the very same subject. Just to give you a background, I was fortunate to do my PhD thesis on an antimalarial drug (artemisinin) with very interesting properties. Artemisinin was developed in early 70s by Chinese scientists. The compound has a short half-life (1-2 hrs), probably low bioavailability (no i.v. formulation available) and consequently high variability in plasma concentrations after oral administration, and induces enzymes already after a single dose. Furthermore, one of its derivatives used in the clinic was shown to cause neurotoxicity in practically all tested animals following i.m. dosing. In other words, artemisinin would most probably not move past early preclinical stages, if it was to be developed in a modern pharma company. However, artemisinin and its derivatives are the best antimalarials available. They are safe, with practically no side-effects in humans, they are potent with a
Back to the Top
I would imagine, based on the number of protozoan, the variability in infected anaimals would be even greater. It would seem that, for drugs binding to targets within the plasma compartment, a different model must be developed.
Back to the Top
Toufigh,
> It is a very interesting question and I have actually been working on and off on a manuscript on the very same subject. Just to give you a background, I was fortunate to do my PhD thesis on an antimalarial drug (artemisinin) with very interesting properties. Artemisinin was developed in early 70s by Chinese scientists. The compound has a short half-life (1-2 hrs), probably low bioavailability (no i.v. formulation available) and consequently high variability in plasma concentrations after oral administration, and induces enzymes already after a single dose. Furthermore, one of its derivatives used in the clinic was shown to cause neurotoxicity in practically all tested animals following i.m. dosing. In other words, artemisinin would most probably not move past early preclinical stages, if it was to be developed in a modern pharma company. However, artemisinin and its derivatives are the best antimalarials available. They are safe, with practically no side-effects in humans, they are potent with
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "PK criteria to continue drug development" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)