Hello,
I tested different drugs for cancer treatment in vitro for now. As I followed so far a previously set up protocol, it just came now into my mind, that the drugs half life might play a more important role than thought considering the duration of treatment before stopping and getting my result.
1) If my drug has a half-life of 50h, does it make sense to test it only 48h or do I definitely need to apply a treatment longer than the half life ?
I think it is better to stay in these hours, to be sure to see the effect of all the drug, in real life, they might give a second dose after the first half-life time's over.....
So if my drug has a half life of 6h, .. I'd rather do a shorter treatment or give a second/third dose ...right?
2) The indicated drug's half -lives are usually referred to the half life in a human body, right? Can I assume that it is the same in vitro? I don't think so.
I would be very grateful for explanations, or links with references,
Opinions in the lab are diverging....
To make short a potentially very long story, yes the half-life (HL) of your drug of interest is a crucial parameter to obtain in vivo anticancer activity.
I do not think that you will obtainan "universal" response (accoding in your lab).
The half-life of your drug in vitro does not relate to its counterpart in vivo because the metabolisation processes are not the same at all.
You should perform murine and human hepatic microsome analyses to have an idea of the half-time of your drug.
If the half-time is "long" (> 24 h in my experience), you should go with oral administration. If the half-time is short, you should go with i.v. administrations.
Thus, you should determine the half-time of your drug in vivo following a single per os versus i.v. injection.
If your per os availability is equal or higher than 25% of the i.v. bioavailability, you can go with oral administrations for your anticancer treatment. Otherwise i.v.
If you go with oral administrations, you should go with one administration (very roughly) every half-time / 2.
With an i.v. administration, every half-time.
But you must first determine the maximal tolerated dose (MTD) in you rodent species.
Once you have determine this MTD parameter (e.g. the dose that kills no mouse / rat in a group of 3-5 individuals after 28 days of observation, and without >20% loss of weight and "adverse clinical / behavioral effects" as compared to the control (untreated but receiving the vehicle + a "true" control group) group), you should administer your compound chronically about ten times after you have observable / measurable tumors every:
* every HT/2 x MTD/2 if oral administrations
* every HT x MTD/4.
The idea is to cover tumor growth with a:
* a one- to two-week treatment and 5-10 i.v. or oral administrations for rapid growing tumors 5-10 days after tumor grafting (depending on the model),
* a three- to four-week treatment for slowly growing tumors.
These are parameters issued from my own experience and I guess that you will obtain soon a "bunch" of other responses!
Good luck
Robert
Robert, Thank you very much for your detailed answer!
For the dugs i will use in vivo I so far planned to work mainly with FDA approved ones, so the MTD and half lifes (HL) in mice are known in the most cases.
My question was more referred to in vitro studies I am doing with these drugs and not approved ones. AS the half life is usually always indicated referring to in vivo, right ?!
I'd need to know how I can from the in vivo HL one come to the in vitro one and then ...is it necessary to do treatments in vitro longer or shorter than the half life, where I think not longer the half life....
Thanks again !
Dear Vanessa,
From my own experience, you cannot infer from in vivo HL to in vitro IC50 / GI50.
In vitro, you should treat your cells according to a "standard" US NCI protocol (see their website). You will be thus able to compare your GI50 profiles to positive controls that you should also assay in your experiments and for which the GI50 data are available from the US NCI database.
It is very unusual to test compounds in vitro taking into consideration HL in vivo parameters.
Best regards
Robert
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