Itraconazole oral 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. 

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... 

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. 

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. 

The oral bioavailability of fluconazole, following administration of cither tablet or oral. suspension do.sagc forms, is excellent. Apparently, the presence of two weakly basic triazole rings in the molecule confers sufficient aqueous solubility to balance the lipophilicity of the 2.4-difluorophenyl group. The oral absorption of fluconazole, in contrast to the oral absorption of ketoconazolc or itraconazole, is not affected by alteration in ga.strointcstinal acidity or the presence of food. 

Figure 3. Predicted DCS classification of Itraconazole (A) as well as the effect of solubility on fraction absorbed (B). The Spider plot suggest good oral bioavailability at solubility values above 100 pg/mL. The solubility of itraconazole at neutral pH is estimated at 1 ng/mL. Itraconazole can be solubilized in 2-hydroxypropyl-p-cyclodextrin to levels in excess of 10 mg/mL which suggests Class I behavior (C). (See color insert after Index.)...

Classification and pharmacokinetics The azoles used for systemic mycoses include ke-toconazole, fluconazole, itraconazole, and voriconazole. Oral bioavailability is variable (normal gastric acidity is required). Hueonazole and voriconazole are more reliably absorbed via the oral route than the other azoles. The drugs are distributed to most body tissues, but with the exception of fluconazole, drug levels achieved in the CNS are low. Liver metabolism is responsible for the elimination of ketoconazole, itraconazole, and voriconazole. Fluconazole is eliminated by the kidneys, largely in unchanged form. 

Carver P, Welage L, Kauffman C. The effect of food and gastric pH on the oral bioavailability of itraconazole in HIV+ patients. Intersci Conf Antimicrob Agents Chemother 996) 36,6. 

Bae SK, Park SJ, Shim EJ, Mun JH, Kim EY, Shin JG, Shon JH. Increased oral bioavailability of itraconazole and its active metabolite, 7-hydroxyitraconazole, when coadministered with a vitamin C beverage... 

The commercially available Sporanox capsule formulation is a solid dispersion relying on the principle of supersaturation to enhance the intestinal absorption of the antifungal itraconazole (ITR), a weak base (pKa = 4) with an extremely low and pH-dependent aqueous solubility (ca. 1 ng/mL in water, 6 mg/mL in 0.1 M HCl). This formulation comprises a molecular dispersion of ITR in a hydroxypropylmethyl-cellulose (HPMC) matrix, which is coated onto inert sugar spheres. Dissolution of HPMC in media simulating the gastric environment results in supersaturated concentrations which are maintained for at least 4 h. HPMC is believed to prevent ITR from precipitation in the stomach and in the intestine, resulting in significant absorption (maximum fraction absorbed ca. 85 %) and oral bioavailability (ca. 55 % Brewster et al. 2008). 

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. 

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. 

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. 

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. 

Nelfinavir mesylate is a peptidomimetic drug that is effective in HIV-1 and HIV-2 wild-type and ZDV-resistant strains, with median effective dose concentrations ranging from 9 to 60 nM (95% effective dose, 0.04 mg/mL) (98). After IV administration, the elimination half-life of nelfinavir was approximately 1 hour. In combination with D4T, nelfinavir reduced HIV viral load by approximately 98% after 4 weeks. It is well tolerated when used with azole antifungals (ketoconazole, fluconazole, or itraconazole) or macrolide antibiotics (erythromycin, clarithromycin, or azithromycin) however, it causes diarrhea and other side effects common to nonnucleoside drugs. Following oral administration, nelfinavir peak levels in plasma ranged from 0.34 mg/mL (10 mg/kg in the dog) to 1.7 mg/mL (50 mg/kg in the rat). In the dog, nelfinavir was slowly absorbed, and bioavailability was 47%. The drug appeared to be metabolized in the liver, and the major excretory route was in feces. 

Recently, Loftsson et al. proposed that CyDs can enhance absorption of Class II as vell as Class IV drugs, whereas CyD can modify oral absorption and/or reduce local irritation by drugs of Classes I and III [52], In fact, we have recently reported that hydrophilic CyDs can enhance the oral bioavailabUity of itraconazol [53] and tacrolimus [33], typical Class II drugs. Additionally j8-CyD is capable of shortening the onset time of action of piroxicam and to reduce the risk of directgastric irritation [54]. Furthermore, DM-a-CyD and 2 also enhance the bioavailability of cyclosporine A, a Class IV drug [55] (see below. Section 14.4.1). 

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