Itraconazole bioavailability

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

Specific antifungals (and their usual dosages) for the treatment of coccidioidomycosis include amphotericin B IV (0.5 to 1.5 mg/kg/day), ketocona-zole (400 mg orally daily), IV or oral fluconazole (usually 400 to 800 mg daily, although dosages as high as 1,200 mg/day have been utilized without complications), and itraconazole (200 to 300 mg orally twice daily as either capsules or solution). If itraconazole is used, measurement of serum concentrations may be helpful to ascertain whether oral bioavailability is adequate. 

Release-related bioavailability problems have been encountered in the pharmaceutical development of formulations for a number of quite different chemical entities, including ciclos-porin, digoxin, griseofulvin, and itraconazole, to name but a few. A thorough knowledge of hydrodynamics is useful in... 

Oral solution/Injectlon The oral bioavailability is maximal when itraconazole oral solution is taken without food. Steady state is reached after 1 to 2 weeks during chronic administration. Peak plasma levels are observed 2 hours (fasting) to 5 hours (with food) following oral administration. Steady-state plasma concentrations are approximately 25% lower when the oral solution is taken with food. 

As a consequence of its high lipophilicity and low aqueous solubility, gastric acidity is also required for itraconazole absorption (Haria et al., 1996). It is best absorbed when administered with food, although there is considerable interpatient variabihty. The oral bioavailability or itraconazole from a 100-mg solution dose was 55%. Like ketoconazole, its bioavailability and half-life are dose-dependent, indicating saturable metabolism. Once absorbed, itraconazole is highly plasma protein bound (99.8%) and widely distributed (10.7 L/kg). Although itraconazole is widely metabolized, it does produce an active metabolite by hydroxylation of the triazolone side-chain. 

Although itraconazole and fluconazole are both triazoles, they are chemically and pharmacologically distinct. Itraconazole (Sporanox) is lipophilic and water insoluble and requires a low gastric pH for absorption. Oral bioavailability is variable, only 50 to 60% when taken with food and 20% or less when the drug is taken on an empty stomach. Itraconazole is highly protein bound (99%) and is metabolized in the liver and excreted into the bile. With initial dosing, the plasma half-life is 15 to 20 hours steady-state serum concentrations are reached only after 2 weeks of therapy, when the half-life is extended to 30 to 35 hours. In lipophilic tissues, drug concentration is 2 to 20 times that found in... 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

Itraconazole (Sporan ), a potent and widely used anitfungal agent, is almost insoluble in water and dilute acid - 5 mg/L). It has very high lipophilicity (mLog= 5.7), and its molecular weight is more than 700. Its absolute bioavailability is around 55% following oral administration. 

However, the food-effect study on Sporaffooral solution in healthy subjects observed that oral bioavailability of itraconazole actually decreased by 31 % under fed condition (Van de Velde et al., 1996). Thus, in its product labeling, it is indicated that SporShoral solution should be taken without a meal to ensure maximal absorption. Further, Spof Dcad solution and capsules should not be used interchangeably. 

Lange D, Pavao JH, Wu J, Klausner M. Effect of cola beverage on the bioavailability of itraconazole in the presence of H2 blockerd.Clin Pharmacol, 1997 37 535-540. 

In a recent review, Shan and Zaworotko have discussed cocrystals having pharmaceutical interest, and presented several case studies that they used to demonstrate how one could enhance the solubility, bioavailability, and/or stability of drug substances [23]. The systems considered were the cocrystals of fluoxetine hydrochloride with carboxylic acids, itraconazole with dicarboxylic acids, sidenafil with acetylsalicylic acid, and melamine with cyanuric acid. One main conclusion advanced by the authors was that the use of cocrystal systems in pharmaceutical dosage forms was inevitable, and that the main questions were who would benefit and how drastic the influence on development would ultimately turn out to be. 

Voriconazole is the newest triazole to be licensed in the USA. It is available in intravenous and oral formulations. The recommended dosage is 400 mg/d. The drug is well absorbed orally, with a bioavailability exceeding 90%, and exhibits less protein binding than itraconazole. Metabolism is predominantly hepatic, but the propensity for inhibition of mammalian P450 appears to be low. Observed toxicities include rash, elevated hepatic enzymes, and transient visual disturbances. 

The original formulation, a buffered powder, has been replaced by chewable and dispersible buffered tablets with greater bioavailability (30-40%) a new enteric-coated formulation further improves patient convenience and tolerability. Since the chewable tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those taking sodium-restricted diets. Didanosine should be taken on an empty stomach and, because of the buffered formulation, should be administered at least 2 hours after administration of drugs requiring acidity for optimal absorption (eg, ketoconazole, itraconazole, dapsone). 

Pharmacokinetics Itraconazole is well-absorbed orally and food increases its bioavailability. It is extensively bound to plasma proteins and distributes well throughout most tissues, including bone, sputum and adipose tissues. However, therapeutic concentrations are not attained in the CSF. Like ketoconazole it is extensively metabolized in the liver but does not inhibit androgen synthesis. Little of the parent drug appears in the urine and thus doses do not have to be reduced in renal failure. 

In terms of ADMET, the absorption of celiprolol from the gastrointestinal tract is rapid, and its time to onset of action is only 30-60 min, with a peak effect in about 2-3 h. The presence of food in the gut can reduce absorption by about 30%. Itraconazole increases, while grapefruit juice significantly decreases, plasma concentrations of celiprolol [138]. Likewise, orange juice substantially reduces the bioavailability of celiprolol, and because it is consumed widely, this interaction is like-... 

CARBAMAZEPINE ANTIFUNGALS - ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE, VORICONAZOLE 1 plasma concentrations of itraconazole and of its active metabolite, ketoconazole, posaconazole and voriconazole, with risk of therapeutic failure, t carbamazepine plasma concentrations These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Carbamazepine is a powerful inducer of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2), and the result is very low or undetectable plasma levels. Inhibition of P-gp t bioavailability of carbamazepine Avoid co-administration of posaconazole or voriconazole with carbamazepine. Watch for inadequate therapeutic effects, and t dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider use of the less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessary to monitor carbamazepine levels... 

AZOLES - FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CORTICOSTEROIDS t adrenal suppressive effects of corticosteroids, which may T risk of infections and produce an inadequate response to stress scenarios Due to inhibition of CYP3A4-mediated metabolism of corticosteroids and inhibition of P-gp (t bioavailability of corticosteroids) Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat... 

ITRACONAZOLE KETOCONAZOLE t itraconazole levels, with risk of toxic effects Ketoconazole is a potent inhibitor of the metabolism of itraconazole by the CYP3A4 and a potent inhibitor of P-gp, which is considered to T bioavailability of itraconazole Warn patients about toxic effects such as swelling around the ankles (peripheral oedema), shortness of breath, loss of appetite (anorexia) and yellow discoloration of the urine and eyes (jaundice), i dose if due to interaction... 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CALCIUM CHANNEL BLOCKERS Plasma concentrations of dihydropyridine calcium channel blockers are t by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may t bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in t bioavailability of diltiazem Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure... 

Itraconazole is a broad-spectrum synthetic triazole that has good oral bioavailability and is less toxic than amphotericin B and ketoconazole.The solution has better bioavailability than the capsule and provides higher plasma concentration levels. Compared with fluconazole and ketoconazole, itraconazole penetrates all ocular tissues poorly when orally administered. Itraconazole can be used as a 1% ophthalmic suspension but is not very effective in treating severe fungal keratitis. 

Itraconazole, an antifungal agent, is an API with very low water solubility so it is marketed as the amorphous form to increase oral bioavailability. Remenar et al. synthesized four cocrystals with a stoichiometry of 2 1 (drug ligand) where the ligand... 

Itraconazole, a weakly basic (pKa 3.7) water-insoluble antifungal drug, is solubilized to lOmg/ml using a combination of 40% hydroxypropyl-p-cyclo-dextrin (i.e., 400mg/ml) in water and pH adjustment to approximately 2 in Sporanox oral solution. The relative oral bioavailability of itraconazole from the oral solution is 149%i 68%i compared to capsules from which the oral bioavailability is 55%). Therefore, the oral bioavailability of itraconazole from the oral solution can be estimated to be 45-82%i. The dose of Sporanox oral solution is up to 20 ml once a day, which is 8.0 g of hydroxypropyl-p-cyclodextrin per dose representing the estimated maximum amount administered orally per dose. 

Barone JA, Moskovitz BL, Guamieri J, Hassell AE, Colaizzi JL, Bierman RH, lessen L. Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers. Antimicrob Agents Chemother 1998 42(7) 1862-5. 

B. Azole antifungals include systemic agents such as keto-conazole, fluconazole, itraconazole, and voriconazole. Topical agents used for the treatment of vaginal candidiasis and thrush include miconazole and clotrimazole. The pharmacologic properties of the systemic azoles differ considerably. Ketoconazole, the first oral azole developed, has poor bioavailability and requires an acidic environment for enhanced absorption. Thus, initial studies required ketoconazole to be administered with a cola to increase bioavailability. Fluconazole, unlike itraconazole and ketoconazole, is hydrophillic and has increased penetration across the blood-brain barrier. Fluconazole is also the only azole that is renally eliminated. 

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