Actions of Itrafungol in details
Synthetic broad-spectrum antifungal.
Pharmacology: Itrafungol, a triazole derivative is active against infections with dermatophytes (Trichophyton and Microsporum spp, Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Pityrosporum sp, Candida sp including C. albicans, C. glabrata and C. krusei), Aspergillus sp, Histoplasma sp, Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea sp, Cladosporium sp, Blastomyces dermatitidis and various other yeasts and fungi.
In vitro studies have demonstrated that Itrafungol impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
Pharmacokinetics: Capsule: The oral bioavailability of Itrafungol is maximal when the capsules are taken immediately after a full meal. Peak plasma levels are reached 3-4 hrs following an oral dose. Elimination from plasma is biphasic with a terminal half-life of 1-1.5 days. During chronic administration, steady state is reached after 1-2 weeks. Steady-state plasma concentrations of Itrafungol 3-4 hrs after drug intake are 0.4 mcg/mL (100 mg once a day), 1.1 mcg/mL (200 mg once a day) and 2 mcg/mL (200 mg twice a day).
The plasma protein-binding of Itrafungol is 99.8%. Concentrations of Itrafungol in whole blood are 60% of those in plasma. Uptake in keratinous tissues, especially the skin, is up to 4 times higher than in plasma, and elimination of Itrafungol is related to epidermal regeneration. In contrast to the plasma levels which become undetectable within 7 days of stopping therapy, therapeutic levels in the skin persist for 2-4 weeks after discontinuation of a 4-week treatment. Levels of Itrafungol have been detected in the nail keratin as early as 1 week after start of treatment and persist for at least 6 months after the end of a 3-month course of therapy. Itrafungol is also present in sebum and to a lesser extent in sweat.
Itrafungol is also extensively distributed into tissues that are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2-3 times higher than the corresponding plasma concentrations.
Therapeutic levels in vaginal tissue are maintained for another 2 days after discontinuation of a 3-day course with 200 mg daily and for another 3 days after discontinuation of a 1-day course with 200 mg twice a day.
Itrafungol is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-Itrafungol, which has a comparable antifungal activity in vitro to Itrafungol. Antifungal drug levels measured by bioassay were about 3 times those of Itrafungol assayed by high-performance liquid chromatography. Faecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is <0.3% of the dose. About 35% of the dose is excreted as metabolites in the urine within 1 week.
Oral Solution:
The oral bioavailability of Itrafungol is maximal when Itrafungol is taken without food. During chronic administration, steady-state is reached after 1-2 weeks. Peak plasma levels are observed 2 hrs (fasting) to 5 hrs (with food) following the oral administration. After repeated once a day administration of Itrafungol 200 mg in fasting condition, steady-state plasma concentrations of Itrafungol fluctuate between 1 and 2 mcg/mL (trough to peak). When the oral solution is taken with food, steady-state plasma concentrations of Itrafungol are about 25% lower.The plasma protein-binding of Itrafungol is 99.8%. Itrafungol is extensively distributed into tissues which are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2-3 times higher than the corresponding plasma concentrations.
Itrafungol is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-Itrafungol which has, in vitro, a comparable antifungal activity to Itrafungol. Plasma levels of hydroxy-Itrafungol are about 2 times higher than those of Itrafungol.
After repeated oral administration, elimination of Itrafungol from plasma is biphasic with a terminal half-life of 1.5 days. Faecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is <0.03% of the dose. About 35% of the dose is excreted as metabolites in the urine within a week.
How should I take Itrafungol?
Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
The Itrafungol capsule should be taken after a full meal.
Take Itrafungol oral solution (liquid) on an empty stomach, at least 1 hour before or 2 hours after a meal. Swish the liquid in your mouth for several seconds before swallowing it.
Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.
The Itrafungol has a special dosing schedule that includes not taking the medicine for several days in a row. Follow all dosing instructions carefully.
Do not crush, chew, break, or open an Itrafungol capsule. Swallow it whole.
Itrafungol capsules should not be used in place of Itrafungol oral solution (liquid) if that is what your doctor has prescribed. Make sure you have received the correct type of this medicine at the pharmacy and ask the pharmacist if you have any questions.
If you also take a stomach acid reducer (Tagamet, Pepcid, Axid, Zantac, and others), take Itrafungol with an acidic drink such as non-diet cola.
Take this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Itrafungol will not treat a viral infection such as the common cold or flu.
While using Itrafungol, you may need frequent blood tests.
Store at room temperature away from moisture, heat, and light.
Itrafungol administration
Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
The Itrafungol capsule should be taken after a full meal.
Take Itrafungol oral solution (liquid) on an empty stomach, at least 1 hour before or 2 hours after a meal. Swish the liquid in your mouth for several seconds before swallowing it.
Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Itrafungol capsules should not be used in place of Itrafungol oral solution (liquid) if that is what your doctor has prescribed. Make sure you have received the correct type of this medication at the pharmacy and ask the pharmacist if you have any questions.
Take this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Itrafungol will not treat a viral infection such as the common cold or flu.
While using Itrafungol, you may need frequent blood tests at your doctor's office.
Store at room temperature away from moisture, heat, and light.
Itrafungol pharmacology
Pharmacokinetics And Metabolism
General Pharmacokinetic Characteristics
Peak plasma concentrations of Itrafungol are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, Itrafungol accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/ml, 1.1 μg/ml and 2.0 μg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of Itrafungol generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, Itrafungol plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itrafungol mean total plasma clearance following intravenous administration is 278 ml/min. Itrafungol clearance decreases at higher doses due to saturable hepatic metabolism.
Absorption
Itrafungol is rapidly absorbed after oral administration. Peak plasma concentrations of Itrafungol are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of Itrafungol is about 55%.
The oral bioavailability of Itrafungol is maximal when Itrafungol® (Itrafungol) Capsules are taken immediately after a full meal. Absorption of Itrafungol capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. Absorption of Itrafungol under fasted conditions in these subjects is increased when Itrafungol® Capsules are administered with an acidic beverage (such as a non-diet cola). When Itrafungol® Capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, Itrafungol absorption was comparable to that observed when Itrafungol® Capsules were administered alone.
Itrafungol exposure is lower with the Capsule formulation than with the
Oral Solution when the same dose of drug is given.
Distribution
Most of the Itrafungol in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the Itrafungol in plasma is present as free drug. Itrafungol is distributed in a large apparent volume in the body ( > 700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.
Metabolism
Itrafungol is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of Itrafungol. The main metabolite is hydroxy-Itrafungol, which has in vitro antifungal activity comparable to Itrafungol; trough plasma concentrations of this metabolite are about twice those of Itrafungol.
Excretion
Itrafungol is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of Itrafungol and the active metabolite hydroxy-Itrafungol account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
As re-distribution of Itrafungol from keratinous tissues appears to be negligible, elimination of Itrafungol from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where Itrafungol can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.
Special Populations
Renal Impairment
Limited data are available on the use of oral Itrafungol in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of Itrafungol was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory
Peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min.
References
- DailyMed. "ITRACONAZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Itraconazole: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Itraconazole: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
