Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antimycotics for systemic use-triazole derivatives, ATC code: J02AC04.

Mechanism of action
Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.

Microbiology
Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A.
ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C.
tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C.
pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data suggest that posaconazole is active against organisms not previously regarded as susceptible to azoles such as the zygomycetes (e.g. species of Absidia, Mucor, Rhizopus and Rhizomucor).

Resistance
Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.
The ECOFF values for posaconazole, which distinguish the wild type population from isolates with acquired resistance, have been determined by EUCAST methodology.

EUCAST ECOFF values:
•   Aspergillus flavus: 0.5 mg/L
•   Aspergillus fumigatus: 0.25 mg/L
•   Aspergillus nidulans: 0.5 mg/L
•   Aspergillus niger: 0.5 mg/L
•   Aspergillus terreus: 0.25 mg/L 
There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do not equate to clinical breakpoints.

Breakpoints
EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:
• Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L
• Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L
• Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L 
There are currently insufficient data to set clinical breakpoints for other Candida species.
Combination with other antifungal agents
The use of combination antifungal therapies should not decrease the efficacy of either posaconazole or the other therapies; however, there is currently no clinical evidence that combination therapy will provide an added benefit.

Pharmacokinetic / Pharmacodynamic relationships
A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens and the effects of food on absorption).

Clinical experience

Summary of posaconazole oral suspension studies
Invasive aspergillosis
Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-comparative salvage therapy trial (Study 0041). Clinical outcomes were compared with those in an external control group derived from a retrospective review of medical records. The external control group included 86 patients treated with available therapy (as above) mostly at the same time and at the same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were considered to be refractory to prior therapy in both the posaconazole group (88 %) and in the external control group (79 %).

As shown in Table 3, a successful response (complete or partial resolution) at the end of treatment was seen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, this was not a prospective, randomised controlled study and so all comparisons with the external control group should be viewed with caution.

Table 3. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive aspergillosis in comparison to an external control group
Posaconazole oral            External control group suspension
Overall Response                      45/107 (42 %)                22/86 (26 %) Success by Species
All mycologically confirmed
Aspergillus spp.1                 34/76          (45 %)        19/74            (26 %) A. fumigatus                  12/29          (41 %)        12/34            (35 %) A. flavus                     10/19          (53 %)        3/16             (19 %) A. terreus                    4/14           (29 %)        2/13             (15 %) A. niger                      3/5            (60 %)        2/7              (29 %) 
Zygomycosis: Successful responses to posaconazole therapy were noted in 7/13 (54%) of patients with zygomycete infections. Sites of infection included the sinuses, lung, and skin.
Organisms included Rhizopus, Mucor and Rhizomucor. Most of the patients had underlying haematological malignancies, half of which required a bone marrow transplant. Half of the patients were enrolled with intolerance to previous therapy and the other half as a result of 

1   Includes other less common species or species unknown
disease that was refractory to prior therapy. Three patients were noted to have disseminated disease, one of which had a successful outcome after failing amphotericin B therapy.

Fusarium spp.
11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole oral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, seven patients were classed as responders.

Chromoblastomycosis/Mycetoma
9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divided doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis
11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of signs and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divided doses for a median of 296 days and up to 460 days.

Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC)
A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with azole-susceptible oropharyngeal candidiasis (most patients studied had C. albicans isolated at baseline). The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).

The clinical response rates from the above study are shown in the Table 4 below.
Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14 as well as 4 weeks after the end of treatment.

Table 4. Clinical success rates in Oropharyngeal Candidiasis
Endpoint                                                Posaconazole                           Fluconazole Clinical success rate at Day 14                       91.7 % (155/169)                      92.5 % (148/160) Clinical success rate 4 weeks after end of treatment 68.5 % (98/143)                         61.8 % (84/136) Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement) divided by the total number of cases eligible for analysis.

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899) Two randomised, controlled prophylaxis studies were conducted among patients at high risk for developing invasive fungal infections.

Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post- randomisation as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The majority (377/600, [63 %]) of patients included had Acute Grade 2 or 3 or chronic extensive (195/600, [32.5 %]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole and 77 days for fluconazole.


Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs at 100 days post-randomisation. New diagnosis of acute myelogenous leukaemia was the most common underlying condition (435/602, [72 %]). The mean duration of therapy was 29 days for posaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 5 and 6 for results from both studies. There were fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients.

Table 5. Results from clinical studies in prophylaxis of Invasive Fungal Infections.
Study                Posaconazole oral               Controla                 P-Value suspension
Proportion (%) of patients with proven/probable IFIs
On-treatment periodb
1899d                                  7/304 (2)               25/298 (8)                              0.0009 316e                                   7/291 (2)               22/288 (8)                              0.0038 Fixed-time periodc
1899d                                 14/304 (5)              33/298 (11)                              0.0031 316 d                                 16/301 (5)               27/299 (9)                              0.0740 FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the baseline day to 111 days post-baseline.
d: All randomised e: All treated

Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections.
Study                Posaconazole oral suspension                       Controla Proportion (%) of patients with proven/probable Aspergillosis
On-treatment periodb
1899d                                         2/304 (1)                                      20/298 (7) 316e                                          3/291 (1)                                      17/288 (6) Fixed-time periodc
1899d                                         4/304 (1)                                      26/298 (9) 316 d                                         7/301 (2)                                      21/299 (7) FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the baseline day to 111 days post-baseline.
d: All randomised e: All treated

In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed [POS 49/304 (16 %) vs. FLU/ITZ 67/298 (22 %) p= 0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomisation, was significantly higher for posaconazole recipients; this survival benefit was demonstrated when the analysis considered all causes of death (P= 0.0354) as well as IFI-related deaths (P = 0.0209).

In Study 316, overall mortality was similar (POS, 25 %; FLU, 28 %); however, the proportion of IFI-related deaths was significantly lower in the POS group (4/301) compared with the FLU group (12/299; P= 0.0413).

Paediatric population

Safety and efficacy in paediatric patients below the age of 18 years have not been established.

Electrocardiogram evaluation
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from 173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the mean QTc (Fridericia) interval from baseline were observed.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Posaconazole is absorbed with a median tmax of 3 hours (fed patients). The pharmacokinetics of posaconazole are linear following single and multiple dose administration of up to 800 mg when taken with a high fat meal. No further increases in exposure were observed when doses above 800 mg daily were administered to patients and healthy volunteers. In the fasting state, AUC increased less than in proportion to dose above 200 mg. In healthy volunteers under fasting conditions, dividing the total daily dose (800 mg) into 200 mg four times daily compared to 400 mg twice daily, was shown to increase posaconazole exposure by 2.6-fold.

Effect of food on oral absorption in healthy volunteers
The absorption of posaconazole was significantly increased when posaconazole 400 mg (once daily) was administered during and immediately after the consumption of a high fat meal (~ 50 grams fat) compared to administration before a meal, with Cmax and AUC increasing by approximately 330 % and 360 %, respectively. The AUC of posaconazole is: 4 times greater when administered with a high-fat meal (~ 50 grams fat) and about 2.6 times greater when administered during a non-fat meal or nutritional supplement (14 grams fat) relative to the fasted state (see sections 4.2 and 4.5).

Distribution
Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of distribution (1,774 litres) and is highly protein bound (> 98 %), predominantly to serum albumin.

Biotransformation
Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to be altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolites observed. The excreted metabolites in urine and faeces account for approximately 17 % of the administered radiolabelled dose.

Elimination
Posaconazole is slowly eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours). After administration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77 % of the radiolabelled dose) with the major component being parent compound (66 % of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14 % of the radiolabelled dose excreted in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state is attained following 7 to 10 days of multiple-dose administration.

Pharmacokinetics in special populations
Children (< 18 years)
Pharmacokinetics in paediatric patients below the age of 18 years have not been established.

Gender
The pharmacokinetics of posaconazole are comparable in men and women.

Elderly (≥ 65 years)
An increase in Cmax (26 %) and AUC (29 %) was observed in elderly subjects (24 subjects  65 years of age) relative to younger subjects (24 subjects 18 - 45 years of age). However, in clinical efficacy trials, the safety profile of posaconazole between the young and elderly patients was similar.

Race
There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in Black subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black and Caucasian subjects was similar.

Weight
Pharmacokinetic modelling with an oral tablet formulation suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.
Patients with a low body weight (< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be closely monitored for adverse events.

Renal impairment
Following single-dose administration of posaconazole oral suspension, there was no effect of mild and moderate renal impairment (n=18, Cl cr ≥ 20 mL/min/1.73 m2) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl cr < 20 mL/min/1.73 m2), the AUC of posaconazole was highly variable [> 96 % CV (coefficient of variance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.

Hepatic impairment
After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child- Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that there is a larger increase in unbound posaconazole exposure than the observed 60 % increase in total AUC. The elimination half-life (t1/2) was prolonged from approximately 27 hours up to ~43 hours in respective groups. No dose adjustment is recommended for patients with mild to severe hepatic impairment but caution is advised due to the potential for higher plasma exposure.