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).

The following in vitro data are available, but their clinical significance is unknown. In a surveillance study of > 3,000 clinical mold isolates from 2010-2018, 90 % of non-Aspergillus fungi exhibited the following in vitro minimum inhibitory concentration (MIC): Mucorales spp (n=81) of 2 mg/L; Scedosporium apiospermum/S. boydii (n=65) of 2 mg/L; Exophiala dermatiditis (n=15) of 0.5 mg/L, and Purpureocillium lilacinum (n=21) of 1 mg/L.


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: 0.5 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
•     Candida dubliniensis: 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.

Clinical experience

Summary of posaconazole tablet bridging study
Study 5615 was a non-comparative multi-centre study performed to evaluate the pharmacokinetic properties, safety, and tolerability of posaconazole tablet. Study 5615 was conducted in a similar patient population to that previously studied in the pivotal posaconazole oral suspension clinical program. The pharmacokinetics and safety data from Study 5615 were bridged to the existing data (including efficacy data) with the oral suspension.

The subject population included: 1) patients with AML or MDS who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patients who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or treatment of GVHD. Two different dosing groups were evaluated: 200 mg twice daily on Day 1, followed by 200 mg once daily thereafter (Part IA) and 300 mg twice daily on Day 1, followed by 300 mg once daily thereafter (Part 1B and Part 2).

Serial PK samples were collected on Day 1 and at steady state on Day 8 for all Part 1 subjects and a subset of Part 2 subjects. Moreover, sparse PK samples were collected at several days during steady state before the next dose (Cmin) for a larger subject population. Based on average C min concentrations, a predicted average concentration (Cav) could be calculated for 186 subjects dosed with 300 mg. PK analysis in patients of Cav found that 81 % of the subjects treated with the 300 mg once daily dose attained steady state predicted Cav between 500-2,500 ng/mL. One subject (<1 %) had a predicted Cav below 500 ng/mL and 19 % of the subjects had a predicted Cav above 2,500 ng/mL. Subjects achieved a mean predicted Cav at steady state of 1,970 ng/mL.

In Table 3 a comparison is shown of exposure (Cav) after administration of posaconazole tablet and posaconazole oral suspension at therapeutic doses in patients depicted as quartile analysis. Exposures after tablet administration are generally higher than, but overlapping with, exposures after administration of posaconazole oral suspension.

Table 3. Cav quartile analyses of pivotal patient studies with posaconazole tablet and oral suspension Posaconazole                      Posaconazole oral suspension tablet
Prophylaxis in       Prophylaxis in     Prophylaxis in        Treatment - AML and HSCT                GVHD            Neutropenia           Invasive Study 5615            Study 316         Study 1899          Aspergillosis Study 0041
300 mg once daily       200 mg three       200 mg three      200 mg four times (Day 1 300 mg          times daily        times daily              daily twice daily)*                                             (hospitalized) then 400 mg twice daily
Quartile              pCav Range            Cav Range          Cav Range            Cav Range (ng/mL)               (ng/mL)            (ng/mL)              (ng/mL) Q1                     442 – 1,223            22 – 557           90 – 322             55 – 277 Q2                    1,240 – 1,710          557 – 915          322 – 490            290 – 544 Q3                    1,719 – 2,291         915 – 1,563         490 – 734            550 – 861 Q4                    2,304 – 9,523        1,563 – 3,650       734 – 2,200          877 – 2,010 pCav: predicted Cav
Cav = the average concentration when measured at steady state
*20 patients received 200 mg once daily (Day 1 200 mg twice daily)


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 study (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 4, 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 4. 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 %) 

1
Includes other less common species or species unknown

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 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.

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 study 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-randomization 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 e
316                                      7/291 (2)                      22/288 (8)                       0.0038 c
Fixed-time period
1899d                                   14/304 (5)                     33/298 (11)                       0.0031 d
316                                     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                        Controla suspension
Proportion (%) of patients with proven/probable Aspergillosis
On-treatment periodb
1899d                                                   2/304 (1)                                20/298 (7) e
316                                                     3/291 (1)                                17/288 (6) c
Fixed-time period d
1899                                                    4/304 (1)                                26/298 (9) d
316                                                     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
Noxafil gastro-resistant tablets are not indicated for children and adolescents aged below 18 years.

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

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).

Absorption
Posaconazole tablets are absorbed with a median Tmax of 4 to 5 hours and exhibits dose proportional pharmacokinetics after single and multiple dosing up to 300 mg.

Following a single dose administration of 300 mg posaconazole tablets after a high fat meal to healthy volunteers, the AUC0-72 hours and Cmax were higher compared to administration under fasted condition (51 % and 16 % for AUC0-72 hours and Cmax respectively).

Posaconazole plasma concentrations following administration of posaconazole tablets may increase over time in some patients. The reason for this time-dependency is not completely understood.

Distribution
Posaconazole, after administration of the tablet, has a mean apparent volume of distribution of 394 L (42 %), ranging between 294-583 L among the studies in healthy volunteers.

Posaconazole 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 after administration of the tablets, is slowly eliminated with a mean half-life (t½) of 29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. 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 plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1).

Pharmacokinetics in special populations
Children (< 18 years)
Noxafil gastro-resistant tablets are not indicated for children and adolescents aged below 18 years.

Gender
The pharmacokinetics of posaconazole tablets are comparable in men and women.
Elderly
The pharmacokinetics of posaconazole tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.


Race
There is insufficient data among different races with posaconazole tablets.

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, in particular those receiving posaconazole after HSCT, who have 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.

Similar recommendations apply to posaconazole tablets; however, a specific study has not been conducted with the posaconazole tablets.

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 (t½) 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.

Similar recommendations apply to posaconazole tablets; however, a specific study has not been conducted with the posaconazole tablets.