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Advocacy Issues > "All substances are poisons"  ...

On the importance of the dose

Last update: 11/07/2017

"All substances are poisons: there is none which is not a poison.
The right dose differentiates a poison and a remedy."
Paracelsus (1493-1541)

 

Dr. Norris:  A new concept may help us at last abandon one-size-fits-all dosing of cancer treatment drugs http://bit.ly/2AiBcuA 

What is it about?

"With many medicines, it is obvious to doctors and patients alike that different people require different doses, and that we cannot predict exactly the right dose for each person before giving the first dose. Thus, a process of gradual dose adjustment over time is needed to learn what dose strikes the best balance between the good and bad effects of the medicine in each individual. Many people who take drugs for high blood pressure, low thyroid or epilepsy will recall having to adjust their dose one or more times when they first started. Certainly, many people with diabetes who inject insulin are experts in this concept, since they are actively involved with dose titration every day of their lives.

This paper is about applying this very same principle to cancer treatment drugs. Currently, a 'one-size-fits-all' mentality dominates dosing in oncology, and this approach gets established very early in the drug development process. The first use of most cancer drugs in humans occurs in people with cancer who have not been doing well despite having tried all standard therapies. People in this situation are often willing to try an experimental drug, even when doctors have no experience to guide them in choosing a dose. The aim of these early 'Phase 1' studies is conceived of as finding 'the' Maximum Tolerated Dose (MTD)—as if there were a single right dose for everyone. Despite its obvious flaws, this fallacy persists because statistical methods have not been available to help us see past it. The aim of this paper is to provide such methods, and to put them in a conceptual context that makes them feasible to implement in clinical trials and in clinical practice.

Why is it important?
For 2 decades, evidence has been accumulating that patients who have adverse effects from their chemotherapy actually tend to get better results from it. (Please see https://www.zotero.org/groups/1150255/the_mtd_kills, where I have collected a list of dozens of journal articles relating to this.) This is not surprising, of course, since the adverse effects experienced by these patients would also have 'hurt' their cancer cells—which is the whole point of chemotherapy. What this means, however, is that better ways of safely finding the strongest acceptable dose for each patient will give people with cancer their best chance to benefit from treatment. This is obviously directly important to each individual person with cancer, but it is also indirectly important for society because inadequate dosing in Phase 2 and Phase 3 clinical trials might stop good drugs from getting approved by regulatory agencies."

 

  •  Dose Escalation Methods in Phase I Cancer Clinical Trials
    Christophe Le Tourneau J. Jack Lee Lillian L. Siu
    JNCI: Journal of the National Cancer Institute, Volume 101, Issue 10, 20 May 2009, Pages 708–720 http://bit.ly/2j6lL4r 

 

On the importance of the dose, and how cancer drugs work - or not work - in the body:

Here in the northeast a storm is brewing, bringing hurricane force winds, accumulating snow … blizzard conditions.    For snow to accumulate, the intensity and duration must be sufficient for the crystals to reach earth, to stick, and to build up faster than they evaporate or melt.  

... These are principles that apply pretty well to the behavior of drugs in the body that are investigated as a first step when a drug is tested in human subjects.  Having a basic understanding of the importance of getting the dose right in clinical research, you will know what to expect in a phase I clinical trial … and also what questions to ask when advised to take an herb to treat a cancer.   

The study compound (to have a chance to be active) must get to the blood – the vehicle for distribution of the compound to the cells in our body.   Then, to have biologic activity, the compound must stick to something  … ideally to a part of the cell involved in the malignant behavior,  such as a receptor (on the cell), or a pathway (in the cell) that drives the abnormal growth or persistence.    Affinity for the target is also important.   Affinity is how well the compound binds to the target … as a key fits a lock.   The better the fit the more likely it is that the compound will remain in place and have an effect on the cell.

In olden days, anti-cancer drugs were identified by trial and error – by screening to see which compounds showed signals of activity in various (and very imperfect) cancer cell models.  Nowadays, the target is identified first, the compound is then designed (shaped) to bind to the target.    For this reason we can anticipate an improved chance of benefiting from participating in phase I cancer trials – depending on the importance of the target.

In drug development, the specificity of the drug to the target is also important.  Does the target also exist in heart or lung cells?  Cell culture and even animal models can’t tell us about this … reliably.  Compounds with the high specificity will bind only to a portion of the tumor cells.  Compounds with low specificity will have many off-target effects … leading to more side effects.  

Will the compound be safe to administer when given at a biologically active dose?    A Paracelsus noted, “The right dose differentiates a poison and a remedy."  Table salt is a poison at high doses.  Compounds found in seasoning may well be toxic if given at high doses or in new ways that allow the compound to reach the blood at therapeutic doses. 

The safety record for phase I trials is very good because of the extra steps to monitor for patient safety.  The patient is followed carefully by monitoring factors in the blood – such as elevated kidney and liver enzymes.   The dose is increased slowly – sometimes in the same patient (intra-patient dose escalation) or in different groups (dose cohorts).   For each participant, blood samples are taken often to check for signals of toxicity and also to carry out  pharmacokinetic studies to learn how the compound behaves in the body. 

Pharmacokinetics (PK) is a core part of legitimate cancer drug study (and is notably missing in Internet claims for the therapeutic use of herbs).  PK is defined as the study of the time course of drug Absorption, Distribution, Metabolism, and Excretion (ADME).   The PK studies help to identify a dose and schedule for next phase of clinical studies – a dose that has a scientifically plausible potential to have therapeutic effects with acceptable toxicity (a mouthful). 

The dose identified in phase I studies is sometimes the maximum tolerated dose (frequently abbreviated as the MDT).  The range of doses that’s found to be active and safe is sometimes called the therapeutic window.  The width of the window is sometimes called the therapeutic index.   A compound with a narrow therapeutic window will require more caution when administered in part because compounds can behave differently in different people - may clear faster or slower in me than in you, for example.

The ADME of PK

A  measures how much of the compound is absorbed into the blood at different doses. 

D  measures the distribution of the compound to  compartments of the body such as the heart, liver, blood, CNS, fat tissue…

M  determine how the compound is changed by metabolic processes.   For some drugs the metabolite (produced by the liver) is what is active (for good or for ill) and not the original compound.

E  measures excretion  … which determines how long the compound lasts in the blood and other compartments, which influences the dose schedule. 

Notes on the limits of preclinical experiments,
the study of compounds in cell culture or laboratory animals:

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Animal models (where cancer cells are implanted in a mouse or other animal) may be used to estimate a safe starting dose for a compound when it’s first tested in humans.
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Anti-cancer activity in test tube experiment may be based on constant exposure to high concentrations of the compound and therefore cannot account for the AMED of PK (how the compound behaves in the body of a person at other concentrations)
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Cancer cells are very difficult to keep alive in a test tube even under the most favorable conditions.  It seems that normal bystander cells are needed to keep lymphoma cells alive.  This is a major barrier to making more rapid progress against cancer.

The cancer cell lines used in preclinical research are also very different than the cancer cells that arise in people.  
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The overwhelming majority of compounds showing activity in test tube experiments do not pan out – are ineffective or too toxic at the biologically active dose.
 
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For compounds taken by mouth, absorption varies a lot.  For example, very little of the herbal compound curcumin is absorbed into the blood when taken orally.   For this reason nano particle delivery is being explored as a way to administer compounds with poor bioavailability.  Will the compound be safe when delivered in high doses into the blood in this way?  What will be the off-target effects?  The delivery method can change the safety profile substantially.
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If made by animal, plant, or by man: the molecular structures of the compounds are identical.  

Being “natural” does not increase the potential for safety or efficacy– it merely describes the source.  Natural compounds made by plants and animals can be as deadly as man-made compounds. 

Compounds (from any source) that do not have side effects, are very unlikely to have treatment effects either.
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Buyer beware that herbal products are not regulated by FDA for purity and may have undeclared additives and contaminants.   The dose on the label is often wrong.  Search for ConsumerLabs for details.
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In theory, compounds (from any source) given at low but biologically active doses can foster treatment resistance.   The low or intermittent exposure to the compound allowing the cells to adapt to develop resistance pathways.  Presumably, this is the reason that research focuses on finding the highest tolerated dose of a new compound … and that protocols usually involve combinations of agents that work by different mechanisms of action.
 End of notes on the importance of dose.  For now : )  

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Related resources:

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Introduction to Pharmacokinetics and Pharmacodynamics ashp.org
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Patents  wikipedia.org 
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Treatment mechanisms | Treatment types 

 

 
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