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REGULATORY SCIENCE |
From the Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research (CDER), Food and Drug Administration, Rockville, MD 20850.
Address for reprints: Shiew-Mei Huang, PhD, Office of Clinical Pharmacology and Biopharmaceutics, HFD-850, Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, PKLN 6A/19, Rockville, MD 20850.
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ABSTRACT |
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 TOP ABSTRACT DRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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Key Words: Drug-drug interaction • drug-dietary supplement interaction • drug-juice interaction • drug development • exposure-response relationship • labeling • risk management
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The increasing use of dietary supplements presents a special challenge in managing patients' health care. In AIDS and cancer patients, the use of multiple prescription drugs and dietary supplements is, in particular, prevalent.2,3 Depending on the level of evidence for the above interactions, the Center for Drug Evaluation and Research (CDER) may make the decision to incorporate information about these interactions in drug labeling as one of the initial steps toward risk communications to health providers and patients.
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DRUG-DRUG INTERACTIONS |
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TOPABSTRACTDRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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In addition to published reports, documents have been developed and are available to provide guidance to industry and agency reviewers regarding the use of various methodologies to investigate drug-drug interactions.13,14 As the science progresses, revision of these documents is necessary to address labeling and other emerging issues.15-17 Recent public workshops and industry working groups have also produced useful information about the evaluation of drug interactions.18,19
The clinical significance of increases or decreases in the systemic exposure of coadministered drugs found in clinical studies conducted in healthy subjects or patient populations should be determined based on the known relationships between dose and/or plasma concentrations and biomarkers of efficacy or safety.20 When evaluating the significance of a pharmacokinetic interaction, it is usually assumed that the pharmacokinetic-pharmacodynamic (PK-PD) relationship of a drug is unchanged in the presence of other drugs. Recommendations based on this relationship can then be made with respect to changing the dose, adjusting the dosing interval, or including suitable language in the labeling, "precautions/warnings," or "contraindications." Figure 1a illustrates that, via evaluation of the relationship between exposure (dose, AUC, Cmax, etc.) and response (key efficacy and safety measures, either clinical endpoints, surrogate endpoints, or valid biomarkers), a range of systemic exposures corresponding to effective and safe administration can be determined. With this information, rational dose adjustments can be made to achieve target systemic exposure when interacting drugs are coadministered. In some cases, it may not be necessary to adjust the dose or dosing regimen as the changes in exposure would still be within the therapeutic range of exposure defined in other clinical trials. Therefore, doses (usually lower) or dosing regimens not tested clinically can be recommended if these adjusted doses or dosage regimens in patients in certain conditions (e.g., presence of an enzyme inhibitor or hepatic dysfunction) would provide similar systemic exposure as that in patients without these conditions. For example, rosuvastatin, a HMG CoA reductase inhibitor, was recently approved for the treatment of hypercholesterolemia and mixed hyperlipidemia. Data from various Phase II clinical trials showed dose-related increases in the extent of low-density lipoprotein (LDL) lowering in patients given 1 to 80mg for 6 weeks.21 There were also dose- or concentration-related increases in the occurrence rates of rhabdomyolysis, myopathy, or proteinuria.22 Based on the efficacy and safety data contained in the new drug application, doses of 5 to 40 mg once daily were approved23 (with a usual recommended starting dose of 10 mg once daily). Figure 1b illustrates the relationship between the approved doses and their efficacy and safety. Table II shows results of some interaction studies and the recommended doses (5-10 mg) of rosuvastatin when patients are to take certain other drugs.23 Table III shows results of key interaction studies and the recommended doses when vardenafil, recently approved for erectile dysfunction, is administered with various cytochrome P450 inhibitors. Note that the approved doses are 5 to 20 mg once per day (with a recommended starting dose of 10 mg). Figure 1c illustrates the relationship between the dose and efficacy and safety. The recommended doses and dosing regimens range from 2.5 mg every 3 days to 5 mg per day24 when vardenafil is administered with cytochrome P450 inhibitors to achieve systemic exposure levels within those known to correspond to safe and effective use of the drug.
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DRUG-DIETARY SUPPLEMENT INTERACTIONS |
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TOPABSTRACTDRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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Following reports of reduced plasma levels of indinavir in healthy subjects when St. John's wort was coadministered,27 as well as reports of heart transplant rejection with corresponding decreases in plasma levels of cyclosporine in patients taking St. John's wort while on cyclosporine,28 the Food and Drug Administration (FDA) issued a health advisory in February 2000 stating that "concomitant use with protease inhibitors or non-nucleoside reverse transcriptase inhibitors is not recommended."29 A search of FDA adverse events reporting databases in both the CDER and the CFSAN (Center for Food Safety and Applied Nutrition) on St. John's wort up to July 2002 resulted in 498 reports, including 42 that implicated St. John's wort's possible role in the varied responses of cyclosporine (rejection, lowered plasma levels), oral contraceptives (breakthrough bleedings, pregnancy), sildenafil (loss of efficacy), and so on.30
Subsequently, the CDER and the FDA Office of Women's Health sponsored prospective clinical studies to understand the underlying mechanisms of interactions between St. John's wort and these drugs. Using a cocktail approach, midazolam (via oral and intravenous administration), caffeine, dextromethorphan, and tolbutamide were administered to healthy human subjects to evaluate activities of CYP3A (intestinal and hepatic), CYP1A2, CYP2D6, and CYP2C9, respectively. St. John's wort appeared to have minimal effects on these enzymes after acute administration (900 mg). In contrast, chronic administration (2 weeks) of St. John's wort (300 mg three times a day) selectively induced CYP3A, with a greater effect in the small intestine than in the liver.31 In a similarly designed study using fexofenadine as a probe drug for the P-gp transporter, acute dosing of St. John's wort slightly increased fexofenadine levels.32 These increases were, however, reduced to baseline after 2 weeks of daily dosing of St. John's wort. Another study evaluating St. John's wort's effects on the clearance of a low-dose oral contraceptive showed that 8 weeks of St. John's wort treatment decreased plasma levels of norethindrone and reduced the t1/2 of ethinyl estradiol,33 consistent with increased CYP3A activity. In this study, more breakthrough bleeding was found in the St. John's wort treatment phase as compared to the control phase (7/12 vs. 2/12). Incidentally, the midazolam clearance measured in this study showed a twofold higher clearance in the subjects with breakthrough bleeding as compared to those without.33
Impact on Drug Labeling
Based on the mechanistic information, the current labeling recommendation is that for drugs that are substrates of CYP3A or P-gp and in which the products' effectiveness may be reduced upon coadministration of St. John's wort, St. John's wort may be listed along with other known inducers, such as rifampin and rifabutin, in the labeling as possibly decreasing plasma levels. For example, Kaletra (lopinavir and ritonavir), Mifeprex (mifepristone, RU486), Nuvaring (etonogestrel/ethinyl estradiol), Gleevec (imatinib), Neoral (cyclosporine), Rapamune (sirolimus), and Prograf (tacrolimus) have information about St. John's wort in various sections of their labeling.34 In addition, several St. John's wort products carry labeling information such as the following: "St. John's Wort can have potentially dangerous interactions with some prescription drugs. Consult your physician before taking St. John's Wort if you are currently taking anticoagulants, oral contraceptives, antidepressants, anti-seizure medications, drugs to treat HIV or prevent transplant rejections, or any other prescription drug."35
Echinacea
Echinacea, often used for the treatment of cold and viral infection, is another one of the top-five selling products in the United States. In vitro liver microsomal studies showed that echinacea may affect the activity of metabolizing enzymes.36 The effect of echinacea on CYP3A, CYP1A2, CYP2D6, and CYP2C9 in healthy human subjects was studied using a cocktail approach as described previously for St. John's wort. After 8 days of administration of 400 mg four times a day of an echinacea product, CYP2C9 and CYP2D6 activities were not changed significantly. On the other hand, CYP1A2 and intestinal CYP3A activities were inhibited while hepatic CYP3A was induced.37 Based on these preliminary findings, the effect of echinacea on various CYP3A substrates may vary depending on the relative contribution of intestinal CYP3A versus the hepatic CYP3A in the individual substrate's clearance pathway to a given drug's overall clearance.
Ginkgo Biloba
Ginkgo biloba, often used for memory improvement, is another one of top-five selling products in the United States. In vitro liver microsomal studies showed that ginkgo products affect the activity of metabolizing enzymes.38 The clinical effect of ginkgo on various metabolizing enzymes has been evaluated with a cocktail approach.38 This ginkgo product (ginkgo biloba extract EGb761) was shown to induce CYP2C19 based on the changes in plasma AUC ratios of a probe drug and its metabolite, omeprazole/5-hydroxyomeprazole. The extent of induction appeared to be CYP2C19 genotype dependent.39
Impact on Clinical Study Design
To avoid variable outcomes due to the uncontrolled use of dietary supplements during clinical trials, it is important to include their use in the exclusion criteria. An example of statements in a study protocol includes the following: "Participants will be excluded for the following reasons:... use of prescription or over-the-counter medications, including herbal products, or alcohol within two weeks prior to enrollment."
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DRUG-CITRUS FRUIT AND OTHER FOOD INTERACTIONS |
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TOPABSTRACTDRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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A search of FDA adverse events ending in January 2002 resulted in 36 cases implicating grapefruit juice in possible interactions. These included cases with observed extension of pharmacological effects for calcium channel blockers (resulting in hypotension), statins (leading to muscle pain), antihistamines (resultant cardiac effects), and others.53 One report indicated that a 69-year-old male on lovastatin (and gemfibrozil, among other medications) developed diffuse muscle pain and a high creatine phosphate kinase level (400-fold higher than normal) within 2 weeks after switching from his usual orange juice to grapefruit juice. The reporting physician suggested interactions between grapefruit juice and lovastatin and gemfibrozil and recommended that the patient avoid grapefruit juice.53-55
Impact on Drug Labeling
The current labeling recommendation is that for drugs that are primarily substrates of CYP3A with low oral bioavailability, grapefruit juice may be listed along with other CYP3A inhibitors, such as ketoconazole and erythromycin, in the labeling as possibly increasing plasma levels of coadministered drugs. For example, cyclosporine, sirolimus, simvastatin, and lovastatin have information on a grapefruit juice interaction in various sections of their labeling.34
Grapefruit Juice, Apple Juice, and Orange Juice Effects on Transporters
Grapefruit juice appears to also inhibit P-gp,56 and this may be one of the mechanisms for the increase in cyclosporine levels when cyclosporine is given with grapefruit juice. Fexofenadine is a P-gp substrate.57 However, instead of increasing plasma levels of fexofenadine, consumption of a large quantity (1200 mL or 40 oz) of grapefruit juice, apple juice, or orange juice, respectively, decreased plasma levels of fexofenadine.12 In vitro evaluations showed that fexofenadine is also a substrate of an uptake transporter in the intestine (OATP) and that fruit juices studied are more potent inhibitors of OATP than P-gp. This may explain the observed decreased fexofenadine plasma levels (Figure 2).
Calcium-Fortified Orange Juice Effect on Bioavailability
Several studies have shown a modest effect of calcium-fortified orange juice on the absorption of fluoro-quinolones. For example, studies on levofloxacin, gatifloxacin, and ciprofloxacin showed that Cmax was decreased by 11%, 15%, and 41%, respectively, when these drugs were given with calcium-fortified orange juice.58-60 Chemical complexation of the floxacins with the calcium ion may play a major role in the reduced absorption and decreased plasma levels. The current labeling for Cipro (ciprofloxacin) tablets has the following information for patients: "As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or sucralfate, Videx® (didanosine)... or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with a meal that contains these products."34
Cranberry Juice
Cranberry juice has been used to reduce the recurrence of urinary tract infection.61 Recently, the British Committee on Safety of Medicines reported five cases of excessive warfarin anticoagulation and implicated cranberry juice as the interacting component. In its report of "current problems in pharmacovigilance,"62 it described one fatal case63 in which a patient's international normalized ratio (INR) was greater than 50 six weeks after starting cranberry juice and warned that "patients taking warfarin should limit or avoid drinking cranberry juice." Although cranberry juice contains antioxidants (flavonoids) that may affect cytochrome P450 enzymes, other factors may have contributed to this case.64 Additional studies will be needed to determine the clinical significance of possible interactions of cranberry juice with drugs that are substrates of various cytochrome P450 enzymes and transporters.
Impact on Clinical Study Design
To avoid variable outcomes due to the uncontrolled use of juices or other foods that may affect various metabolizing enzymes and transporters during clinical trials, it is important to consider their exclusion during the study period. Depending on the clearance pathway of the drug being evaluated, statements in a study protocol may include the following: "For at least 2 weeks prior to the start of the study until its conclusion, volunteers will not be allowed to eat any food or drink any beverage containing alcohol, grapefruit or grapefruit juice, apple or orange juice, vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, mustard), and charbroiled meats."
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INTERACTION STUDIES IN SPECIFIC POPULATIONS |
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TOPABSTRACTDRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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Pharmacogenetics
Many metabolizing enzymes are polymorphically distributed. This may account for the large intersubject variability observed in plasma levels and responses of certain drugs that are substrates of these enzymes. For example, genetic variability in the activity of cytochrome P450 enzymes (e.g., CYP2D6, CYP2C9, CYP2C19, and CYP3A5), Phase II metabolizing enzymes (e.g., UGT1A1 and TPMT), and transporters (e.g., ABCA1, ABCB1, and ABCC) has been reported. Subjects with different genotypes may show a different extent of interactions. For example, a study evaluating the effect of diphenhydramine, a modest CYP2D6 inhibitor, on metoprolol pharmacokinetics showed an increase (60%) in the plasma AUC of metoprolol in CYP2D6 extensive metabolizers (EMs). In contrast, little or no significant changes (10%) in AUC were observed in poor metabolizers (PMs).67 More recently, the labeling of atomoxetine (Strattera), a CYP2D6 substrate, states, "For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs" and "coadministration of cytochrome P450 inhibitors to PMs (poor metabolizers) will not increase the plasma concentrations of atomoxetine."34 In another example, Chow et al38,39 showed that when ginkgo biloba was given with a cocktail of probe drugs for various cytochrome P450 enzymes, ginkgo induced omeprazole clearance to different degrees in different genotypes of CYP2C19. The genotype of the major metabolizing enzyme can influence the extent of interaction of the drug with inhibitors of minor pathways. For example, Brynne et al68 showed that in CYP2D6 poor metabolizers, the clearance of tolterodine, which is mainly metabolized by CYP2D6 with a small contribution by CYP3A, was significantly reduced by a CYP3A inhibitor, ketoconazole.
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CONCLUSIONS |
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TOPABSTRACTDRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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With the increased understanding of the mechanisms of drug interactions of certain dietary supplements (e.g., St. John's wort) and juices (e.g., grapefruit juice), one can project the likelihood of an interaction with a drug depending on the drug's clearance pathway. However, unlike drug products in which the content and interacting components are better understood, information on the active components (responsible for drug interactions) and the contents of dietary supplements and juices is limited. Therefore, current labeling recommendations to avoid drug-dietary supplements and drug-fruit juice interactions are more restrictive than those for drug-drug interactions. As shown in Tables II, III, IV, certain drug-drug interactions can be managed by adjusting the dose or dosing interval of interacting drugs. However, drug-dietary supplement or drug-juice interactions may only be managed by recommending avoidance of their concomitant use when the interactions are deemed clinically significant. With increased understanding of interacting mechanisms12,26,31,32,36-39,51,52,70 and the characterization of the various active components in dietary supplements and juices, as well as their pharmacokinetics,71 more specific guidance to address these interactions in the future may be possible.
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Despite the increased understanding and documentation of drug interactions in the labeling and in letters to "dear health care professionals," well-understood drug interactions continue to be reported.72-74 To address this critical issue of translating information to practice, the CDER has published a proposed rule on a physician's labeling format whereby drug interactions that are significant—or their absence, when they are expected to occur—would appear in the Highlights section, in addition to having this information in the main body of the labeling.17 Additional measures to address patient risks from drugs (e.g., medication guides, restricted distribution, prescriber certification) have been recommended in recently issued draft documents on risk management.75
In conclusion, with continued improvement in our understanding of the mechanisms of interactions and contributions of additional patient factors (e.g., genetics, gender), the risks associated with these interactions can be better predicted, assessed, and managed to reduce the frequency of clinically significant adverse drug reactions.
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FOOTNOTES |
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Submitted for publication January 2, 2004; Revised version accepted March 15, 2004.
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REFERENCES |
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TOPABSTRACTDRUG-DRUG INTERACTIONSDRUG-DIETARY SUPPLEMENT...DRUG-CITRUS FRUIT AND OTHER...INTERACTION STUDIES IN SPECIFIC...CONCLUSIONSREFERENCES |
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