Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic classification
Antimycotics for systemic use, triazole derivatives
ATC code: J02A C02
Itraconazole, a triazole derivative, has a broad spectrum of activity.

In vitro studies have demonstrated that itraconazole 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.

Using CLSI methods, interpretive breakpoints for itraconazole have not been established for Candida species and filamentous fungi.

For itraconazole, breakpoints have only been established by CLSI for Candida spp. from superficial mycotic infections (CLSI M27-A2). The CLSI breakpoints are as follows: susceptible <0.125; susceptible, dose- dependent 0.25-0.5 and resistant >1 µg/mL. Interpretive breakpoints have not been established for the filamentous fungi.

EUCAST breakpoints for itraconazole have been established for Aspergillus flavus, A. fumigatus, A.
nidulans and A. terreus, and are as follows: susceptible <1 mg/L, resistant >1 mg/L. EUCAST breakpoints for itraconazole have been established for Candida albicans and C. dubliniensis, and are as follows: susceptible ≤ 0.06 mg/L,resistant > 0.06 mg/L. EUCAST breakpoints for itraconazole have been established for Candida parapsilosis and C. tropicalis, and are as follows: susceptible ≤ 0.125 mg/L, resistant > 0.125 mg/L. Interpretive breakpoints have not been established by EUCAST for Candida glabrata, C. krusei, C. guilliermondii, Cryptococcus neoformans, Aspergillus niger, and Non-species related breakpoints for Candida and Aspergillus.

EUCAST breakpoints have yet to be established for itraconazole and Candida spp.

In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤1 µg/ml. These include: 
Candida spp. (including Candida albicans, Candida tropicalis, Candida parapsilosis and Candida dubliniensis), Aspergillus spp., Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp., including H. capsulatum, Paracoccidioides brasiliensis, Talaromyces (formerly Penicillium) marneffei, Sporothrix schenckii and Trichosporon spp. Itraconazole also displayed activity in vitro against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp. and various other yeasts and fungi.

Candida krusei, Candida glabrata and Candida guillermondii are generally the least susceptible.
Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.

The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.

Azole resistance appears to develop slowly and is often the result of several genetic mutations.
Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross-resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole- resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties
General pharmacokinetic characteristics
Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole 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 itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Absorption
Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral capsule dose. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal.

Absorption of itraconazole 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 (see section 4.4 Special Warnings and Precautions for use, and section 4.5 Interactions).
Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola).
When itraconazole capsules were administered as a single 200 mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone. (See section 4.5 Interactions.)

Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (See section 4.4 Special Warnings and Precautions for use.) 
Distribution
Most of the itraconazole 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 itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700L), suggesting its 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, is up to four times higher than in plasma. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.

Metabolism
Itraconazole is extensively metabolised 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 itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.

Excretion
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabelled dose, fecal excretion of unchanged drug varies between 3 - 18% of the dose.

Special Populations

Hepatic impairment:
Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in average Cmax (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects.

Data are not available in cirrhotic patients during long-term use of itraconazole. (See section 4.2 Posology and method of administration, and section 4.4 Special warnings and precautions for use.)


Renal impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment.
A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) 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. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.

After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20- 49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects, (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively.) Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.

Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See also section 4.2 Posology and method of administration, and section 4.4 Special warnings and precautions for use.)


Pediatrics
Limited pharmacokinetic data are available on the use of itraconazole in the pediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, Cmax and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.