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Ketoconazole
January 8, 2010
Ketoconazole is a complex drug that kills prostate cancer by
several different methods. Because of this ketoconazole may be
used effectively in a range of different medical conditions.
The purpose of this essay is to provide you with an understanding
of these various situations. We also hope to provide you with
a series of simple rules that help you use ketoconazole effectively.
Ketoconazole has an important role in four distinct clinical
settings:
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Rapid suppression of testosterone. Short of surgical
removal of the testicles, ketoconazole provides the most
rapid reduction of testosterone. There are times when a
patient presents with newly diagnosed prostate cancer that
threatens immediate harm or may even be lethal. For example,
the cancer may have blocked urine outflow from the kidneys
and caused kidney failure. Another example would be cancer
pressing on the spinal cord and threatening paralysis.
High dose ketoconazole can cause a significant drop in
testosterone within 30 minutes and 75% suppression by 24
hours. |
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Killing hormone-resistant prostate cancer. By 1989 it
had already been shown that ketoconazole could effectively
kill prostate cancer cells that were able to grow rapidly
in the complete absence of testosterone. Today this represents
its most common use. Ketoconazole is most widely used in
patients with extensive metastatic disease who have failed
LHRH agonists such as Lupron, Zoladex, Eligard or Trelstar,
where about 33% of the patients can have a dramatic response
with PSA declines of greater than 50%. However, the response
rate can be much higher if treatment is started while the
cancer volume is still low. For example, Drs. Steve Strum
and Mark Scholz have reported a response rate that is much
higher. Additionally, when the PSA is under 10 ng/m, responses
are much more durable with the average duration of 25 months. |
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Ketoconazole can combine with other cancer treatments
to cause very useful responses. Eric Small’s group
at UCSF reported a 75% response rate in hormone-refractory
prostate cancer to the combination of ketoconazole and
Leukine. Chris Logothetis’s group at MD Anderson
has reported impressive responses when ketoconazole is
combined with the chemotherapy agent, doxorubicin. Ketoconazole
blocks two proteins, p-glycoprotein and CYP3A4, that are
involved in resistance to many chemotherapy drugs. This
property has not yet been fully exploited in clinical trials. |
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Ketoconazole is one of the least expensive drugs used
to treat prostate cancer. We are entering a time when the
cost of cancer treatment will be a major issue. One ketoconazole
pill costs a bit more than $2.00. Low dose ketoconazole
involves the use of 3 pills a day for a cost $6 a day or
$180 per 30-day month. Since this drug is most commonly
used to treat hormone-refractory prostate cancer, the other
treatment option is often taxotere-based chemotherapy.
The total cost for that form of chemotherapy can easily
approach $10,000 or more per month. |
Key to Effectively Using Ketoconazole
Unfortunately, ketoconazole is not a simple drug to use. There
are several issues that need to be addressed if you are to receive
maximal benefit. For ketoconazole to be effective, it must reach
the blood stream in high enough concentrations to kill the cancer
cells. Furthermore, these blood levels have to be maintained
day in and day out.
The first problem is that ketoconazole is rapidly destroyed by
the liver. By 8 hours, in most patients blood levels will be
too low to be effective. For this reason, it must be given at
least every 8 hours to give optimal results. I see it being administered
three times a day-- breakfast, lunch and dinner. If breakfast
is at 8 AM and dinner is at 6 PM, this gives 14 hours between
doses with at least 6 of those hours with inadequate drug levels.
The problem with every 8 hours is that one way or another it
gets in the way of sleep for most patients. For example, if the
first dose of the day is at 7 AM, the other doses will fall 3
PM and 11 PM.
The second problem is that the stomach must be adequately acidic
for ketaconazole to be well absorbed. Many men are on drugs to
reduce their stomach acid. For example, heart burn or gastroesophageal
reflux is common and usually treated by proton pump inhibitors
like Nexium, Prilosec, Aciphex, Prevacid, Protonix, and related
drugs. Others take antiacids like Tums. In these situations,
stomach acid will drop low enough to lessen absorption of ketoconazole
from the stomach into the blood stream. Similarly, if you take
ketoconazole with food, the food can lessen the acidity of the
stomach and lessen ketoconazole absorption. There are two approaches
to this problem. One is to take something to increase the acid
content of the stomach. Fruit juice can do this as they are generally
quite acid. Sodas like Coke or Pepsi are also often quite acid.
Vitamin C is ascorbic acid and will do fine at doses of 500-1,000
mg. Here it is important to avoid buffered vitamin C where the
acidity has been neutralized. The other approach is to increase
the dose of ketoconazole sufficiently to overcome the decrease
in absorption. Some physicians recommend ketoconazole be taken
on an empty stomach. I find that that causes so much nausea and
gastric distress that most patients are unwilling to continue
the drug.
The third problem is that ketoconazole interacts poorly with
half of all prescription drugs. Most drugs are removed from the
body by being destroyed in the liver. In the liver, the protein
most important in this process goes by the name of CYP3A4, which
as implied above, is involved in destroying half of all prescription
drugs. If you are on ketoconazole, these other drugs will not
be destroyed as fast as they normally would and their blood levels
will become much higher. This means that normal doses of these
other drugs can become quite toxic. Interestingly, this is the
same pathway by which grapefruit interacts with drugs. There
are several ways to handle this problem. The Physican’s
Desk Reference is another excellent resource: for most modern
drugs this book will tell you if the drug interacts with ketoconazole,
grapefruit or CYP3A4. This PDR is issued each year and is currently
available through Amazon. Phamacy
Times recently had a very comprehensive,
if highly technical, listing of the drugs involved. You can approach
this problem in two ways. First, you can just change the drugs
you are taking to versions that do not interact with ketoconazole.
For example, Lipitor does interact with ketoconazole, so you
can switch to Pravacol or Crestor which do not appear to present
a problem. The second approach is to compensate by reducing the
dose of the drugs that interact with ketoconazole. This is particularly
useful if there are no appropriate alternatives available. In
practice, I find myself very often in this latter situation.
The fourth problem is that people differ widely in how rapidly
their livers destroy ketoconazole. This means that a dose that
might be very toxic for one patient might cause no side effects
in another. I have seen some patients who have only minor side
effects at a dose of 800 mg every 8 hours while every now and
then I encounter a patient who cannot tolerate 100 mg every 8
hours. In my practice, we start men on 200 mg every 8 hours.
After a period of time, if no side effects develop, we will increase
the dose, usually half a tablet every 8 hours, until they develop
mild fatigue. This generally avoids many of the serious side
effects this drug can cause: at the higher doses side effects
can be more severe than chemotherapy.
The fact that people vary in how they handle ketoconazole does
mean that for best use, drug dosing does have to be individualized.
As we have just discussed, I prefer to adjust the dose so that
I give the maximal dose a patient can tolerate with mild to modest
fatigue. The other approach that has been advocated is to measure
ketoconazole blood levels and increase or decrease the dose to
hit a target blood level.
References:
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Harris, K.A., V. Weinberg, R.A. Bok, M. Kakefuda, and
E.J. Small, Low dose ketoconazole with replacement doses
of hydrocortisone in patients with progressive androgen
independent prostate cancer. J Urol, 2002. 168(2): p. 542-5. |
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Blum, R.A., et al., Increased gastric pH and the bioavailability
of fluconazole and ketoconazole. Ann Intern Med, 1991.
114(9): p. 755-7. |
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Lelawongs, P., et al., Effect of food and gastric acidity
on absorption of orally administered ketoconazole. Clin
Pharm, 1988. 7(3): p. 228-35. |
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Boxenbaum, H., Cytochrome P450 3A4 in vivo ketoconazole
competitive inhibition: determination of Ki and dangers
associated with high clearance drugs in general. J Pharm
Pharm Sci, 1999. 2(2): p. 47-52. |
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