Background
Drug interactions can arise with virtually any antifungal therapy and occur primarily in the gastrointestinal tract, liver and kidneys by several distinct mechanisms. The majority of drug interactions are pharmacokinetic in nature, resulting in changes in the absorption or elimination of the interacting drug as well as the antifungal agent [922]. In the GI tract, changes in pH, complexation with ions, or interference with transport and enzymatic processes in the intestinal lumen can interfere with drug absorbance. Induction or inhibition of metabolism in the liver can inhibit or accelerate, respectively, drug clearance from the body. In the kidney, decreases in glomerular filtration, active tubular secretion or other mechanisms can slow renal elimination resulting in excessive drug exposure [922]. Therefore, any patient receiving antifungal therapy should be carefully monitored for potentially severe drug interactions.
Interactions of Drug Absorption
Ketoconazole and itraconazole are weak bases, virtually insoluble in water, and are ionized only at a low pH. Consequently, dissolution and absorption of these compounds is heavily dependent on acidic gastric conditions in the stomach [922, 1291]. Drugs that increase gastric pH (e.g., H2 antagonists, proton pump inhibitors) slow the dissolution of the solid dosage forms and decrease drug available for absorption in the intestinal lumen. Pharmacokinetic studies have documented 30-60% reductions in serum itraconazole concentrations (Cmax, AUC0-24) in healthy volunteers administered itraconazole capsules with either famotidine or omeprazole [1115, 1147, 1345]. Absorption of the solution formulation of itraconazole, however, is not substantially reduced by drugs that increase gastric pH [922].
Antacids, metal ion containing drugs (e.g., sulcralfate), and vitamin supplements can also slow dissolution and absorption of ketoconazole or itraconazole through binding or chelation interactions that impair transport of the drug across the intestinal epithelium [151, 922].
Once a drug reaches the intestinal lumen, it is susceptible to the actions of a variety of plasma membrane transporters and metabolic enzymes located in intestinal enterocytes. Two mechanisms have been identified as important modulators of pre-systemic clearance for azole antifungals such as ketonazole and itraconazole. The first mechanism is P-glycoprotein (P-gp)- a versatile drug transporter found on the apical plasma membrane surface of enterocytes that functions as a “detoxification” pump that expels drug back into the intestinal lumen [972] . Hence, the role of the pump is to limit absorption of potentially toxic lipophilic substances through the intestinal lumen. Azoles such as ketoconazole or itraconazole can be both substrates and inhibitors of the P-gp; making the effects of P-gp efflux on azole absorption difficult to predict in individual patients [972].
The second major mechanism of pre-systemic clearance of azole antifungals involves intestinal metabolism of lipophilic molecules by the cytochrome P450 (CYP) 3A4 enzymes, which result in inactive and active metabolites [972] Similar to P-gP, azole antifungals are both substrates and inhibitors of CYP3A4 enzymes suggesting that P-gP and CYP3A4 work in a coordinated fashion to prevent the absorption of xenobiotics. The degree of intestinal CYP3A4 differs from patient to patient and is not under coordinate expression of CYP3A4 in the liver, which is the principal site of drug metabolism and (presumably) clinically significant interactions affecting drug metabolism [1377].
The principal site for drug metabolism is the liver where lipophilic compounds are transformed into ionized metabolites for renal elimination. This transformation or metabolism generally occurs via two different types of reactions: 1) Phase I (non-synthetic) reactions, which include oxidation, reduction and hydrolysis, and 2) Phase II (synthetic) reactions resulting from conjugation with other molecules (e.g., glucoronidation, sulfation) to improve aqueous solubility [1159]. Interference of drug metabolism through these pathways by induction, suppression, or inhibition of drug metabolism accounts for some of the most common and potentially severe drug interactions encountered in the clinic.
Cytochrome P450 and Antifungal Drug Interactions
Phase I oxidative reactions are an important mechanism for biotransformation of azole antifungals [922]. Most oxidative reactions are catalyzed by a superfamily of mixed-function mono-oxygenases called the cytochrome P40 system. Nomenclature for the enzymes in this system is designated by the abbreviation “CYP” followed by an Arabic number indicating the enzyme family, a capital letter to define the enzyme sub-family, and then a number to describe the enzyme. Allelic forms (alternate forms of the gene) are designated by and asterisk and a number or number-letter combination.
Although 14 human families of CYP enzymes have been identified, approximately 95% of all drug oxidation occurs through the action of 6 CYP enzymes: CYP1A2, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 [1159, 2458].
Considerable variability in CYP enzyme activity may be observed between patients due to medical, environmental, and dietary factors [972, 1377, 2458]. Additional variability in oxidative metabolism arises from genetic polymorphisms (non-random genetic mutations) that can be found in subpopulations of patients for specific CYP enzymes. Specifically, clinically-significant genetic polymorphisms in CYP metabolism have been described for CYP2D6, CYP2C9, and CYP2C19 [1159]. The frequency of polymorphisms also differs among different racial populations. Voriconazole pharmacokinetics, for example, are clearly affected by polymorphisms in CYP2C19 [1092, 1134]. Subpopulations of patients who are homozygous poor metabolizers through the CYP2C19 pathway may experience, on average, 4-fold higher serum concentrations of voriconazole compared to other patients who are heterozygous extensive, or homozygous extensive metabolizes (majority of the population) [1134]. This poor metabolizer CYP 2C19 genotype is found in 1-3% of the Caucasian population, and 15-20% of the Asian population [1159, 2458].
All of the azole-class antifungals currently licensed by the FDA are metabolized to some degree by the CYP P450 system. However, the type of CYP metabolism and degree to which the azole is metabolized is governed by a number of factors including the physiochemical properties of the drug (lipophilicity) and pharmacokinetics. Because ketconazole and itraconazole are highly lipophilic, their clearance is heavily dependent upon metabolism through several CYP 450 pathways including CYP 3A4. Fluconazole, on the other hand, is relatively less lipophilic and requires less CYP transformation at lower dosages (< 200 mg/day) for clearance from the body [922]. Co-administration of azoles with drugs that induce or accelerate strongly CYP-450 metabolism, particularly CYP 3A4, can result in low [1647] or undetectable levels of the azole antifungal [285, 628]. Higher antifungal dosages (particularly of ketoconazole, itraconazole, voriconazole) cannot overcome this interaction.
All azoles are also reversible inhibitors of CYP enzymes in humans [922]. This inhibition is probably a collateral effect of their antifungal mechanism, namely inhibition of 14-alpha-demethylase- a CYP P450 enzyme in fungi involved in the biosynthesis of ergosterol. Once again, the degree and type of inhibition varies with each azole on the basis of its physiochemical characteristics and pharmacokinetics. The most important drug interactions seen with azole antifungals typically arise from inhibition of CYP 3A4, which plays a critical role in the metabolism of a broad array of drug therapies used for cardiovascular disease, endocrine disorders including hyperglycemia, anaesthesia, psychiatric disorders, epilepsy, cancer chemotherapy, and treatment of infectious diseases. A general description of the more common and important drug interactions is summarized below.
Overview of Common Drug Interactions with Antifungal Therapy
| Effect | Mechanism | Antifungals Involved | Suggested clinical management |
|---|---|---|---|
| Decreased serum concentration of azole | Antacids | H2 | |
| Receptor antagonism | Proton Pump Inhibitors | Sulcrafate | Didanosine (oral) |
| Decreased dissolution/absorption of solid dosage form | Ketoconazole, itraconazole (capsules) |
Use solution formulation of itraconazole or other azole if indicated (i.e. voriconazole) Avoid taking antacids within 2 hours of oral azole therapy |
|
| Increased metabolism of azole | Isoniazid Rifampin Phenytoin Carbamazepine |
Phenobarbital | Ritonavir (voriconazole) |
| Induction of mammalian cytochrome-P450 mediated metabolism of azole | Ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole |
Avoid concomitant use of these agents if possible. May require switch to amphotericin B formulation or echinocandin | |
| Increased serum concentration of co-administered drug or metabolite | Oral hypoglycemics S-warfarin R-Wafarin Cyclosporin Tacrolimus Phenytoin Carbamazepine Triazolam, alprazolam, midazolam Diltiazem Lovastatin Isoniazid Rifampin Rifabutin Quinidine Protease inhibitors |
(saquinavir, ritonavir) | Busulifan Vincristine Cyclophosphamide Digoxin Loratidine |
| Inhibition of cytochrome P450, P-gp, or both | Ketoconazole, itraconazole, voriconazole > fluconazole (usual doses) |
Avoid concomitant use if possible. Severity of possible interaction is drug-dependent. Consult prescribing information of each drug to address interaction severity | |
| Increased accumulation of renally-cleared drugs and/or drug vehicles | Flucytosine Fluconazole Beta-lactams and many others… |
||
| Decrease in glomerular filtration | Amphotericin B | Consult package insert. Most drug dosages can be adjusted based on estimates of glomerular filtration (i.e. creatinine clearance). Use of a lipid amphotericin B formulation may help stabilize or slow declines in renal function. | |
| Enhanced nephrotoxicity | Aminoglycosides Cyclosporine |
Intravenous Contrast Dye Foscarnet and others… |
|
| Enhanced glomerular and tubular toxicity in the kidney | Amphotericin B | Minimize co-administration of nephrotoxic agents whenever possible. Consider first-line use of lipid amphotericin B formulation. |