May 13, 2002

The use of high dose Ketoconazole (HDK) is an accepted and viable treatment when basic hormone therapy and anti-androgen withdrawal have been tried and their usefulness exhausted. This is described in detail in the accompanying paper on HDK.

Low Dose Ketoconazole Studies & Results

An alternative to HDK is low dose Ketoconazole(LDK). A study by Harris, Small et al(1), using one half the usual dose (600 mg/day as 200mg 3x/day instead of 1200mg/day) has been done. There were 28 AIPC patients in the study. These patients also received hydrocortisone (HC), which may have improved the response rate. The dose of HC was 20mg AM and 10mg PM. A response rate of 55% PSA response (declining PSA) was achieved. This is in the range of that obtained in the high dose treatment. The duration of response appears to be similar also. The advantage of the lower dose is that the side effects are more easily tolerated. The obvious question to this writer is whether the duration of response will be as good as the high dose. This is not addressed in this study. The study also reports that use of the higher dose after the low dose or upon initial failure was not beneficial. Given the small numbers it’s not clear that this observation can be used as a guide.

Lower doses of ketoconazole have also been used successfully by Oh and Kantoff.(2) They also note that increased gastric pH (less acidic) decreases ketoconazole absorption and recommend taking it on an empty stomach in the absence of histamine receptor type 2 blockers or antacids. Also, they note that the use of hydrocortisone is not always needed, especially at the low dose described here unless adrenal insufficiency is observed.

NOTE: Adrenal insufficiency. Signs and symptoms are low blood pressure, weight loss, weakness, anorexia or nausea, salt craving, diarrhea(or constipation). If the cause is adrenal failure there will be hyperpigmentation, if the cause is pituitary disease usually with "china skin". Treatment is replacement of glucocorticoids and occasionally mineralocorticoids.

Absorption of Ketoconazole

A related issue, which comes up in men attempting to use HDK is the need for an acidic environment in the stomach for maximum absorption. For those who have sensitive stomachs or are on acid blockers this is a problem.

A study by Chin et al(4) perhaps can shed some light on what can be done. In particular, their study used an acidic beverage(coca-cola classic) to increase the acidity (lower pH) to less than the pH of 4.0 that is required for proper absorption. The average drug absorption result thus obtained is about 65% of that of a normal subject not taking an acid blocker.

Note: pH=7 is neutral, less than 7 is acidic and greater than 7 is basic. The pH of blood is about 7.2 or slightly basic. Also, pH of Coca-Cola Classic = 2.5, Pepsi 2.5, Diet Coca-Cola 3.2 and Diet Pepsi 3.2, Diet Minute Maid Orange Juice 3.0.

The value of 65% is similar to that studied in the low dose ketoconazole trial and therefore drinking a coca-cola or pepsi is a viable method of dealing with the artificially induced acid free environment. It should be noted that acid suppression being used here is that produced by a prescription acid blocker such as Axid, Zantac or Prilosec not an over the counter antacid such as Tums or Rolaids. These products will buffer both natural acid and any consumed and should be avoided.

Another suggestion for increasing the gastric acidity that has been suggested, (for which the author has not seen any study data), is the use of chewable vitamin C (1000mg or more) to increase acidity. Witjes et al(3) used 2-3 grams of vitamin C as the acidic substance to take with the ketoconazole.

It should also be noted that in the Chin et al study(4) using an acidic beverage there was a wide range of results, which means that for someone who is not initially responding to the therapy a blood test might be in order to see if there are absorption problems.

Note: A serum concentration of ketoconazole of 4ug/mL is required to achieve a castrate level of testosterone.(3)

NOTE: The above information is provided by a patient not a physician and is only for educational purposes. Take any questions you have to your doctor and review them to your mutual satisfaction.

References

1. Katherine A. Harris, Eric Jay Small, Mark W Frohlich, Robert Bok, Margaret Randall, Mika Kakefuda, University of California San Francisco, San Francisco, CA. ASCO 2001 Abstract # 2419. Published as: Harris, KA et al, "Low Dose Ketoconazole with Replacement Doses of hydrocortisone in patients with Progressive androgen Independent Prostate Cancer, ", The Journal of Urology, Vol 168, 542-545, August 2002.

2. Oh WK and Kantoff PW, "Management of Hormone Refractory Prostate Cancer: Current standards and future prospects,", The J. of Urology, Vol. 160, 1220-1229, October 1998. See page 1224 (Pub Med id # 9751323)

3. Witjes, FJ, et al, Ketoconazole High Dose in Management of Hormonally Pretreated Patients with Progressive Metastatic Prostate Cancer, UROLOGY, May 1989 Volume 23, Number 5, PP 411-415. (Pub Med id # 2652864)

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