Can Zytiga be Used at Just 1 Tablet Daily ?

Long-term use of abiraterone acetate at 250 mg/d: is this really viable?

It has been suggested that, after an initial “loading dose” for a period of time, abiraterone acetate could potentially be used to treat metastatic, castration-resistant prostate cancer (mCRPC) at a much lower daily maintenance dose than that currently approved.
In two messages left on this site (on February 2 and on February 4, 2012), Prof. Gerry Potter (one of the original developers of abiraterone acetate) has stated his opinion that, after initial treatment with a “loading dose” of abiraterone acetate at 1,000 mg/d for a period of 1 month, many patients could potentially be managed with a much lower daily (maintenance) dose of this agent at just 250 mg/d.
We have the greatest respect for Dr. Potter as a medicinal chemist, and we feel very sure that his opinion is based on data available to him that gives him confidence in this clinical strategy … but, we feel it is important to note the following:

• We know of no large-scale clinical trial that has ever tested this concept in men with metastatic prostate cancer.
• No completed, ongoing, or proposed trial of abiraterone acetate currently listed on the ClinicalTrials.gov web site has tested or appears to be designed to test this concept.
• The currently approved dose of abiraterone acetate (in the treatment of men with mCRPC who have previously received at least one cycle of docetaxel-based chemotherapy, in both the USA and Europe) is four 250 mg tablets of abiraterone acetate once daily for a total daily dose of 1,000 mg/d — in combination with prednisone at a dose of 5 mg twice daily.
• Dr. Potter is not a physician, and he does not treat patients with prostate cancer. He is a medicinal chemist with considerable experience in the development of therapeutic agents for the treatment of cancer and other disorders.

Having carefully stated these facts, we have to say that the concept presented by Dr. Potter is intriguing. Abiraterone acetate at a dose of 250 mg/d was tested clinically in a very small number of patients in Phase I trials, and data on the pharmacokinetics of this dose level were reported by Ryan et al. in 2010. It was the lowest dose of the drug used in these early stage trials and may well have significant clinical activity after an appropriate loading dose.
However, we really have no idea whether such a clinical strategy would have the same level of effectiveness as the currently recommended and approved dose of abiraterone. It also seems unlikely that the manufacturer of abiraterone would be interested in testing such a concept. This does not, of course, mean that others could not implement a clinical trial to test the concept; after all, maintenance with a lower dose of abiraterone might impact any cumulative side effects of this agent and would most certainly impact the cost of treatment with this drug over time. One also has to ask whether use of such a maintenance dose level of abiraterone acetate could be associated with a reduction in the daily dose of predisone (which would reduce the impact of the side effects of corticosteroid therapy as well).
We wish to be extremely clear that The “New” Prostate Cancer InfoLink is not recommending (and is in no position to recommend) the use of abiraterone acetate at anything other than the dose approved by regulatory authorities in the USA and Europe. We are merely responding to the suggestion made previously by Prof. Potter.

10 Responses

1. gerald Chodak, on February 6, 2012 at 10:54 am said:

   Your comments are perfect! Any doctor prescribing a lower dose of the drug would be subject to liability issues in the event a patient did not do well, so it is highly unlikely that the lower dose will ever be an issue. One wonders, however, whether testing a lower dose in men with a rising PSA without metastases would be worthwhile.
   
2. JimWaldenfels, on February 6, 2012 at 4:20 pm said:

   HOW ABOUT BIOMARKERS TO MONITOR CONTINUED FAVORABLE RESPONSE AT LOWER DOSE, PRESCRIBED “OFF-LABEL”?
   In the meantime, I hope that some physicians, at the request of patients, will make wise and prudent use of off-label prescription procedures to try the lower dose proposed by Prof. Potter, with careful monitoring of biomarkers. I suspect that is already happening. If it does happen, I'm hopeful that some of those doctors will carefully track results and share them via published papers.
   It would be nice if we patients, scientists, and physicians could wait until that day comes when all the science lines up perfectly and clear guidelines are published. However, patients with challenging cases, like me and the mCRPC patients, often lack the luxury of time!
   
3. Charles (Chuck) Maack, on February 6, 2012 at 9:09 pm said:

   No particular comment other than both Sitemaster’s and Jim’s comments are well explained. With the cost of abiraterone/Zytiga at four 250 mg tablets daily somewhat prohibitive and this protocol apparently lasting somewhere between six and eight weeks before ending and then monitoring continuing results, the subsequent prescribing of Zytiga/abiraterone at a lower dose and monitored for continued effectiveness appears to be to be a reasonable “maintenance” protocol.
   
4. Tom, on February 6, 2012 at 10:45 pm said:

   I think oncologists are more flexible with the abiraterone dose than many might realize. My dad is prescribed 500 mg a day WITH food as opposed to 1,000 mg a day in a fasting state. The rational is taking the medication with food will induce more absorption of the drug; at least equivalent as the dose tested in the clinical trial in a fasting state. Its common sense people, and this drug is expensive. For half the price, his PSA has dropped 80% after 2 months of treatment.
   
5. Ralph Valle, on February 6, 2012 at 11:01 pm said:

   For what is worth … I know a patient that was on the 1000 mg dose for 2 months. He had a PSA reduction response of 95% (10.5 to 0.5 ng/ml). At that point he reduced the dose (on his own) to 500 mg. Now with PSA trending down (0.2) he is contemplating going to 250 mg/day. This patient has used ketoconazole before and was able to titrate the dose to fit his need. Now he is doing the same while saving mega $$$s. This fits with Dr. Potter’s advice.
   
6. Sitemaster, on February 6, 2012 at 11:05 pm said:

   Dear Tom:
   There is a reason that it is recommended that abiraterone acetate not be taken with food. I quote from the instructions to patients:
   “Take ZYTIGA® on an empty stomach. Do not take ZYTIGA® with food. Taking ZYTIGA® with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects.”
   It is certainly possible that by cutting the dose to 500 mg/d one may be able to avoid the risk of excessive side effects, but there are no data to support such a clinical strategy, and there are therefore unknown risks associated with this strategy. “Common sense” may have great value under appropriate circumstances, but not everything that appears to make “common sense” is necessarily sensible in retrospect.
   Over the years, clinicians have done all sorts of things that appeared at the time (at least to the physicians concerned) to make “common sense” (e.g., “cupping,” deliberate bleeding of patients, treatment with arsenic and mercury, I could go on for hours). There are a whole host of such “common sense” treatments that we would consider to be horrifically bad medical practice today.
   Obviously I am pleased to hear that this strategy is working for your father to date … but please beware of generalizations.
   
7. Dr Potter, on February 10, 2012 at 6:09 am said:

   This discussion has raised another question and that is, “Can abiraterone be taken with food?”
   This is a somewhat controversial area, so I will give my opinion as a pharmacologist rather than as a doctor.
   The manufacturer’s prescribing instructions for abiraterone (see section 5.4, Food Effect) state clearly that it should not be taken with food:
   “ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone C_max and AUC_0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.”
   This is because the clinical data for this disease indication has been conducted at a dose of 1 g daily taken without food.
   It is worth re-stating the fact that abiraterone is an exceedingly potent drug, so that it has always surprised me when such high doses (1 gram) of abiraterone acetate are used. Abiraterone is five times more potent than letrozole (Femera), an aromatase inhibitor used to treat breast cancer, which is taken at a daily dose of 20 mg. So why isn’t abiraterone taken at a dose of 20 mg. The main reason is the poor uptake of abiraterone acetate in the un-fed state. Abiraterone acetate has been specially formulated as the acetate to help increase intestinal absorption and bioavailability through absorption by digestion. Without food digestion, there is poor absorption. The main reason for such high doses is therefore due to the very poor absorption of abiraterone acetate by the intestine in the un-fed state. Given on an empty stomach, only about 5% of abiraterone is absorbed by the intestine, so for a 1 g (1000 mg) dose only about 50 mg is absorbed and the remaining 950 mg is excreted. What a waste of drug when 95% is excreted. It would make far better sense if the absorption of the drug can be increased somehow, as is found when the drug is taken with food. Abiraterone was designed as an orally active drug, and as such was designed to be absorbed with food. When abiraterone is taken with food, the absorption increases dramatically — by 10-fold. The area under the curve (AUC) exposure is a measure of the volume of the drug absorbed into the bloodstream and this increased 10-fold when abiraterone was administered with a meal. So it is important to realise that the concentration of abiraterone in the body increases 10-fold when taken with food. In this way a 100 mg dose will deliver the same amount of drug as a 1000 mg dose without food. This means a dose as low as 100 mg could be taken with food to deliver the same pharmacological effect as 1000 mg without food.
   Since it appears that some clinicians are already administering abiraterone with food, it should be borne in mind that a single tablet dose of 250 mg taken with food will deliver 2.5 times more drug than 4 tablets taken without food.
   
8. Sitemaster, on February 10, 2012 at 7:55 am said:

   Thanks Dr. Potter. This is very helpful for people.
   
9. Frank Flynn, on February 10, 2012 at 5:10 pm said:

   I have been on a Zytiga/prednisone regime for almost 2 months now. The treatment seems to be having little or no effect and my PSA continues to rise. Admittedly I have a very aggressive PCa (Gleason 10, Stage IV mCRPC).
   I would be very interested in trying smaller doses, say 250 mg taken with food and will approach my oncologist about this at our next meeting. I have little hope that he will go along with this because of the general reluctance of physicians to expose themselves to litigation. So if he opposes the idea, I believe I will experiment on my own with reduced dosage plus food. I believe I have very little to lose by doing so. The advanced state of my disease leaves me very few options to explore. Thank you Dr. Potter for your information. That and some of the testimony of readers will help me make a final decision.