(ATN) Grapefruit Juice and Saquinavir

(ATN) Grapefruit Juice and Saquinavir

AIDS TREATMENT NEWS Issue #235, November 17, 1995 \
John S. James

Saquinavir, the protease inhibitor developed by Hoffmann-La Roche (and recently recommended for approval by the FDA Antiviral Advisory Committee despite general agreement that the dose which will be approved is too low) has very low bioavailability -- only about 4% of the drug taken orally reaches the general circulation. This is partly because the drug is poorly absorbed, and partly because it is rapidly destroyed by an enzyme (cytochrome P450 3A4, also called CYP3A4) which is present in the liver and also in the intestinal wall. Some drugs and even foods inhibit this enzyme, thus increasing the AUC (area under the curve, a measure of total exposure to the drug) of saquinavir. In studies conducted by Hoffmann-La Roche, the prescription drug ketoconazole increased the AUC -- but ketoconazole would not be used for this purpose because of its toxicity. Ranitidine (Zantac) also increased the AUC of saquinavir, but by an unknown mechanism. [On the other hand, rifampin greatly REDUCED the AUC of saquinavir, and therefore these two drugs should not be combined.]

Chemicals in grapefruit juice also inhibit CYP3A4. Hoffmann- La Roche tested grapefruit juice with saquinavir in 12 HIV- negative volunteers. When they took a 150-ml glass of ordinary reconstituted frozen grapefruit juice with the saquinavir, and then another 150-ml glass an hour later, the AUC of saquinavir was increased to 150% (a 50% increase) [90% confidence interval, 101% to 191%, meaning that if the true value were in fact 150, the variation of the data was such that the observed value would be within that range 90% of the time]. When they used double strength grapefruit juice (reconstituted from the frozen, but with less water) in the same amount and schedule, the AUC of saquinavir was increased to 220% (slightly more than doubled) [90% confidence interval, 161%-300%].

In published studies with other drugs, grapefruit juice usually had comparable effects.(1-7) Some of these studies used 200 ml or 250 ml of fresh-frozen grapefruit juice, taken with the drug, but no dose an hour later. Orange juice had no effect. When the bioflavonoid naringin -- the component of grapefruit juice which was suspected to be the active ingredient in increasing the bioavailability of these drugs -- was tried instead of grapefruit juice, it had much less effect than the juice itself.

Should saquinavir be taken with grapefruit juice, to help make the low dose more effective? Using grapefruit juice might increase the blood level achieved, but also it could have uncertainties and drawbacks. First, the effect of grapefruit juice on drug bioavailability can vary greatly from person to person -- and in addition, each batch of grapefruit juice can be different. Also, there is no way to find out whether or not grapefruit juice is working for oneself, because the test to measure saquinavir in the blood is not commercially available.

Another concern is that some other drugs are also metabolized by the same liver enzyme -- for example, cyclosporine, some calcium channel blockers, theophylline, and others -- and large amounts of grapefruit juice might increase the blood levels of these drugs enough to cause toxicity. Also, the amount of double-strength grapefruit juice required to double the AUC of saquinavir might be irritating to the stomach and hard to tolerate every day. And the "safety database" -- the number of people who already have used saquinavir at higher blood levels -- is small. Due to such concerns, Hoffmann-La Roche decided not to pursue using grapefruit juice, but instead is developing its new formulation of saquinavir, which increases bioavailability about 300%.

Note: Regardless of grapefruit juice, saquinavir must be taken after a meal. The official recommendation, in the Drug Usage Plan of the international compassionate treatment program, is that "Saquinavir should be taken with water within 2 hours after food. Saquinavir should not be taken on an empty stomach." Saquinavir is not affected by stomach acidity; but if taken on an empty stomach, bioavailability is greatly reduced.

References

1. Hukkinen SK, Varhe A, Olkkola KT, and Neuvonen PJ. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. CLINICAL PHARMACOLOGY AND THERAPEUTICS. August 1995; volume 58, number 2, pages 127- 131.

2. Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, and Krahenbuhl S. Interaction between grapefruit juice and midazolam in humans. CLINICAL PHARMACOLOGY AND THERAPEUTICS. July 1995; volume 58, number 1, pages 20-28.

3. Ducharme MP, Warbasse LH, and Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. CLINICAL PHARMACOLOGY AND THERAPEUTICS. May 1995; volume 57, number 5, pages 485-491.

4. Yee GC, Stanley DL, Pessa LJ, and others. Effect of grapefruit juice on blood cyclosporin concentration. LANCET. April 15, 1995; volume 345, pages 955-956.

5. Merkel U, Sigusch H, and Hoffmann A. Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY. 1994; volume 46, number 2, pages 175-177.

6. Baily DG, Arnold JMO, Strong HA, Munoz C, and Spence JD. Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics. CLINICAL PHARMACOLOGY AND THERAPEUTICS. December 1993; volume 54, number 6, pages 589-593.

7. Baily DG, Arnold JMO, Munoz C, and Spence JD. Grapefruit juice--felodipine interaction: Mechanism, predictability, and effect of naringin. CLINICAL PHARMACOLOGY AND THERAPEUTICS. June 1993; volume 53, number 6, pages 637-642.
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