Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole and tetrazole derivative, ATC code: J02AC05

Mechanism of action

Isavuconazole is the active moiety formed after oral or intravenous administration of isavuconazonium sulfate (see section 5.2).


Isavuconazole demonstrates a fungicidal effect by blocking the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase, responsible for the conversion of lanosterol to ergosterol.
This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane, thus weakening the structure and function of the fungal cell membrane.

Microbiology

In animal models of disseminated and pulmonary aspergillosis, the pharmacodynamic (PD) index important in efficacy is exposure divided by minimum inhibitory concentration (MIC) (AUC/MIC).
No clear correlation between in vitro MIC and clinical response for the different species (Aspergillus and Mucorales) could be established.

Concentrations of isavuconazole required to inhibit Aspergillus species and genera/species of the order Mucorales in vitro have been very variable. Generally, concentrations of isavuconazole required to inhibit Mucorales are higher than those required to inhibit the majority of Aspergillus species.


Clinical efficacy has been demonstrated for the following Aspergillus species: Aspergillus fumigatus, A. flavus, A. niger, and A. terreus (see further below).

Mechanism(s) of resistance

Reduced susceptibility to triazole antifungal agents has been associated with mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase involved in ergosterol biosynthesis. Fungal strains with reduced in vitro susceptibility to isavuconazole have been reported, and cross-resistance with voriconazole and other triazole antifungal agents cannot be excluded.

EUCAST Breakpoints

Aspergillus species                 Minimal Inhibitory Concentration (MIC) breakpoint (mg/L) ≤S (Susceptible)                     >R (Resistant)
Aspergillus flavus                                  1                                  2 Aspergillus fumigatus                               1                                  2 Aspergillus nidulans                              0.25                                0.25 Aspergillus terreus                                 1                                  1 
There are currently insufficient data to set clinical breakpoints for other Aspergillus species.

Clinical efficacy and safety
Treatment of invasive aspergillosis
The safety and efficacy of isavuconazole for the treatment of patients with invasive aspergillosis was evaluated in a double-blind, active-controlled clinical study in 516 patients with invasive fungal disease caused by Aspergillus species or other filamentous fungi. In the intent-to-treat (ITT) population, 258 patients received isavuconazole and 258 patients received voriconazole. CRESEMBA was administered intravenously (equivalent to 200 mg isavuconazole) every 8 hours for the first 48 hours, followed by once-daily intravenous or oral treatment (equivalent to 200 mg isavuconazole).
The protocol-defined maximum treatment duration was 84 days. Median treatment duration was 45 days.


The overall response at end-of-treatment (EOT) in the myITT population (patients with proven and probable invasive aspergillosis based on cytology, histology, culture or galactomannan testing) was assessed by an independent blinded Data Review Committee. The myITT population comprised 123 patients receiving isavuconazole and 108 patients receiving voriconazole. The overall response in this population was n = 43 (35%) for isavuconazole and n = 42 (38.9%) for voriconazole. The adjusted treatment difference (voriconazole−isavuconazole) was 4.0 (95% confidence interval: −7.9; 15.9).

The all-cause mortality at Day 42 in this population was 18.7% for isavuconazole and 22.2% for voriconazole. The adjusted treatment difference (isavuconazole−voriconazole) was −2.7% (95 % confidence interval: −12.9; 7.5).

Treatment of mucormycosis
In an open-label non-controlled study, 37 patients with proven or probable mucormycosis received isavuconazole at the same dose regimen as that used to treat invasive aspergillosis. Median treatment duration was 84 days for the overall mucormycosis patient population, and 102 days for the 21 patients not previously treated for mucormycosis. For patients with probable or proven mucormycosis as defined by the independent Data Review Committee (DRC), all-cause mortality at Day 84 was 43.2% (16/37) for the overall patient population, 42.9% (9/21) for mucormycosis patients receiving isavuconazole as primary treatment, and 43.8% (7/16) for mucormycosis patients receiving isavuconazole who were refractory to, or intolerant of, prior antifungal therapy (mainly amphotericin B-based treatments). The DRC-assessed overall success rate at EOT was 11/35 (31.4%), with 5 patients considered completely cured and 6 patients partially cured. A stable response was observed in an additional 10/35 patients (28.6%). In 9 patients with mucormycosis due to Rhizopus spp., 4 patients showed a favourable response to isavuconazole. In 5 patients with mucormycosis due to Rhizomucor spp., no favourable responses were observed. The clinical experience in other species is very limited (Lichtheimia spp. n=2, Cunninghamella spp. n=1, Actinomucor elegans n=1).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Isavuconazonium sulfate is a water-soluble prodrug that can be administered as an intravenous infusion or orally as hard capsules. Following administration, isavuconazonium sulfate is rapidly hydrolysed by plasma esterases to the active moiety isavuconazole; plasma concentrations of the prodrug are very low, and detectable only for a short time after intravenous dosing.

Absorption
Following oral administration of CRESEMBA in healthy subjects, the active moiety isavuconazole is absorbed and reaches maximum plasma concentrations (Cmax) approximately 2–3 hours after single and multiple dosing (see Table 3).

Table 3 Steady state pharmacokinetic parameters of isavuconazole following oral administration of CRESEMBA
Parameter                          Isavuconazole 200 mg            Isavuconazole 600 mg Statistic                                (n = 37)                         (n = 32) Cmax (ng/mL)
Mean                                       7499                            20028 SD                                        1893.3                           3584.3 CV %                                       25.2                             17.9 tmax (h)
Median                                      3.0                              4.0 Range                                    2.0 – 4.0                        2.0 – 4.0 AUC (h•ng/mL)
Mean                                            121402                             352805 SD                                              35768.8                            72018.5 CV %                                             29.5                                20.4 
As shown in table 4 below, the absolute bioavailability of isavuconazole following oral administration of a single dose of CRESEMBA is 98%. Based on these findings, intravenous and oral dosing can be used interchangeably.

Table 4 Pharmacokinetic comparison for oral and intravenous dose (Mean) ISA 400 mg oral               ISA 400 mg i.v.
AUC (h•ng/mL)                           189462.8                      193906.8 CV %                                      36.5                          37.2 Half-life (h)                              110                          115 
Effect of food on absorption
Oral administration of CRESEMBA equivalent to 400 mg isavuconazole with a high-fat meal reduced isavuconazole Cmax by 9% and increased AUC by 9%. CRESEMBA can be taken with or without food.

Distribution
Isavuconazole is extensively distributed, with a mean steady state volume of distribution (Vss) of approximately 450 L. Isavuconazole is highly bound (> 99%) to human plasma proteins, predominantly to albumin.

Biotransformation
In vitro / in vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT), are involved in the metabolism of isavuconazole.

Following single doses of [cyano-14C] isavuconazonium and [pyridinylmethyl-14C] isavuconazonium sulfate in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a number of minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC > 10% of total radio-labelled material.

Elimination
Following oral administration of radio-labelled isavuconazonium sulfate to healthy subjects, a mean of 46.1% of the radioactive dose was recovered in faeces, and 45.5% was recovered in urine.

Renal excretion of intact isavuconazole was less than 1% of the dose administered.

The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites.

Linearity/non-linearity
Studies in healthy subjects have demonstrated that the pharmacokinetics of isavuconazole are proportional up to 600 mg per day.

Pharmacokinetics in special populations

Renal impairment
No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in subjects with mild, moderate or severe renal impairment compared to subjects with normal renal function. Of the 403 patients who received CRESEMBA in the Phase 3 studies, 79 (20%) of patients had an estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. No dose adjustment is required in patients with renal impairment, including those patients with end-stage renal disease.
Isavuconazole is not readily dialysable (see section 4.2).

Hepatic impairment
After a single 100 mg dose of isavuconazole was administered to 32 patients with mild (Child-Pugh Class A) hepatic insufficiency and 32 patients with moderate (Child-Pugh Class B) hepatic insufficiency (16 intravenous and 16 oral patients per Child-Pugh class), the least square mean systemic exposure (AUC) increased 64% in the Child-Pugh Class A group, and 84% in the Child-Pugh Class B group, relative to 32 age- and weight-matched healthy subjects with normal hepatic function.
Mean plasma concentrations (Cmax) were 2% lower in the Child-Pugh Class A group and 30% lower in the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy subjects and patients with mild or moderate hepatic dysfunction demonstrated that the mild and moderate hepatic impairment populations had 40% and 48% lower isavuconazole clearance (CL) values, respectively, than the healthy population.

No dose adjustment is required in patients with mild to moderate hepatic impairment.

Cresemba has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks.
See sections 4.2 and 4.4.