Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XK52 
Mechanism of action
Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and abiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic dependencies in patients with mCRPC and HRR gene mutations.

Niraparib
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis and cell death.

Abiraterone acetate
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor.
Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in, and is required for, androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see section 4.4).

Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.
Androgen deprivation therapies, such as treatment with luteinising hormone releasing hormone Akeega-50/500_mg_100/500_mg_Film Coated Tablets_PI_09_2024
(LHRH) analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).

Pharmacodynamic effects
Abiraterone acetate
Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis.

Clinical efficacy and safety
First-line treatment of mCRPC patients with BRCA 1/2 mutations
The efficacy of Akeega was established in a randomised placebo-controlled multicentre Phase 3 clinical study of patients with mCRPC, MAGNITUDE (Study 64091742PCR3001).

MAGNITUDE was a Phase 3, randomised, double-blind, placebo-controlled, multicentre study that evaluated treatment with the combination of niraparib (200 mg) and abiraterone acetate (1000 mg) plus prednisone (10 mg) daily versus AAP standard of care. Efficacy data are based on Cohort 1 that consisted of 423 patients with mCRPC and select HRR gene mutations, who were randomised (1:1) to receive either niraparib plus AAP (N=212) or placebo plus AAP (N=211) orally daily. Treatment was continued until disease progression, unacceptable toxicity, or death.

Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior AAP (up to 4 months) and ongoing ADT, were eligible. Plasma, blood, and/or tumour tissue samples for all patients were tested by validated next generation sequencing tests to determine germline and/or somatic HRR gene mutation status. There were 225 subjects with a BRCA1/2 mutation enrolled in the study (113 received Akeega). There were an additional 198 patients with a non-BRCA1/2 mutation (ATM, CHEK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) enrolled in the study (99 received Akeega).

The primary endpoint was radiographic progression free survival (rPFS) as determined by blinded independent central radiology (BICR) review based on Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 (soft and tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Time to symptomatic progression (TSP), time to cytotoxic chemotherapy (TCC), and overall survival (OS) were included as secondary efficacy endpoints.

In the All HRR Population, the primary efficacy results with a median follow-up of 18.6 months showed statistically significant improvement in BICR-assessed rPFS with a HR =0.729 (95% CI: 0.556, 0.956; p=0.0217).

Table 4 summarises the demographics and baseline characteristics of BRCA patients enrolled in Cohort 1 of the MAGNITUDE study. The median PSA at diagnosis was 41.07 ug/L (range 01-12080).
All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. All patients who had not received prior orchiectomy continued background androgen deprivation therapy with a GnRH analogue.

Table 4:      Summary of demographics and baseline characteristics in the MAGNITUDE study Cohort 1 (BRCA)
Akeega+P1      Placebo+AAP1        Total
N=113             N=112          N=225 n (%)             n (%)         n (%)
Age (years)
< 65                                               39 (34.5)         37 (33.0)         76 (33.8) ≥ 65-74                                            44 (38.9)         52 (46.4)         96 (42.7) ≥ 75                                               30 (26.5)         23 (20.5)         53 (23.6) 
Akeega-50/500_mg_100/500_mg_Film Coated Tablets_PI_09_2024
Median                                                        67.0                  68.0              68.0 Range                                                        45-100                43-88             43-100 Race
Caucasian                                                  78 (69.0)             84 (75.0)          162 (72.0) Asian                                                      18 (15.9)             20 (17.9)          38 (16.9) Black                                                       3 (2.7)                  0               3 (1.3) Unknown                                                    14 (12.4)              8 (7.1)            22 (9.8) Stratification factors
Past taxane-based chemotherapy exposure                    26 (23.0)             29 (25.9)          55 (24.4) Past AR-targeted therapy exposure                           6 (5.3)               5 (4.5)           11 (4.9) Prior AAP use                                              30 (26.5)             29 (25.9)          59 (26.2) Baseline disease characteristics
Gleason score ≥ 8                                          83 (74.1)             72 (64.3)          155 (69.2) Bone involvement                                           99 (87.6)             93 (83.0)          192 (85.3) Visceral disease (liver, lung, adrenal gland,
26 (23.0)             22 (19.6)          48 (21.3) other)
Metastasis stage at initial diagnosis (M1)                 70 (61.9)             50 (44.6)          120 (53.3) Median time from initial diagnosis to
2.00                 2.31               2.26 randomisation (years)
Median time from mCRPC to first dose
0.27                 0.28               0.27
(years)
BPI-SF pain score last score before first dose)
0                                                          57 (50.4)             57 (50.9)          114 (50.7) 1 to 3                                                     51 (45.1)             40 (35.7)          91 (40.4) >3                                                          5 (4.4)              15 (13.4)           20 (8.9) ECOG Performance Status Score
0                                                          69 (61.1)             80 (71.4)          149 (66.2) 1                                                          44 (38.9)             32 (28.6)          76 (33.8) 
1
P=prednisone or prednisolone

A statistically significant improvement in BICR-assessed rPFS was observed in the primary analysis for BRCA subjects treated with niraparib plus AAP, compared with BRCA subjects treated with placebo plus AAP. Key efficacy results in the BRCA population are presented in Table 5. The Kaplan- Meier curves for BICR assessed rPFS in the BRCA population are shown in Figure 1.

Table 5:    Efficacy results from the BRCA population of the MAGNITUDE study Akeega+P1              Placebo+AAP1
Endpoints                                             (N=113)                  (N=112) Radiographic Progression-free Survival   2

Event of disease progression or death (%)           45 (39.8%)               64 (57.1%) Median, months (95% CI)                           16.6 (13.9, NE)          10.9 (8.3, 13.8) Hazard Ratio (95% CI)                                       0.533 (0.361, 0.789) p-value                                                           0.0014 Overall Survival3
Hazard Ratio (95% CI)                                       0.788 (0.554, 1.120) 1
P=prednisone or prednisolone
2
Primary analysis/Interim analysis (data cut-off: 08OCT2021), with 18.6 months median follow-up 3 Final Analysis (data cut-off: 15May2023), with 35.9 months median follow-up NE = Not estimable



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Figure 1:       Kaplan-Meier Plot of BICR assessed radiologic progression-free survival in the BRCA population (MAGNITUDE, primary analysis)

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Co-administration of niraparib and abiraterone has no impact on the exposures of the individual moieties. The AUC and Cmax are comparable for niraparib and abiraterone when administered as Akeega regular strength (100 mg/500 mg) film-coated tablet or as combination of individual components when compared to respective monotherapy exposures.

Absorption
Akeega
In mCRPC patients, under fasted and modified fasted conditions, upon administration of multiple doses of Akeega tablets, the maximum plasma concentration was achieved within a median of 3 hours for niraparib, and a median of 1.5 hours for abiraterone.

In a relative bioavailability study, the maximum (Cmax) and total (AUC0-72h) exposure of abiraterone in mCRPC patients (n=67) treated with Akeega lower strength film-coated tablets (2 x 50 mg/500 mg) was 33% and 22% higher, respectively, when compared to exposures in patients (n=67) taking individual single agents (100 mg niraparib capsule and 4 x 250 mg abiraterone acetate tablets) (see section 4.2). The inter-subject variability (%CV) in exposures were 80.4% and 72.9%, respectively.
Niraparib exposure was comparable between Akeega lower strength film-coated tablets and single agents.

Niraparib
The absolute bioavailability of niraparib is approximately 73%. Niraparib is a substrate of P- glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with medicinal products that inhibit these transporters is unlikely.

Abiraterone acetate
Abiraterone acetate is rapidly converted in vivo to abiraterone (see section 5.1).

Akeega-50/500_mg_100/500_mg_Film Coated Tablets_PI_09_2024
Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in highly variable exposures.
Therefore, abiraterone acetate must not be taken with food.

Distribution
Based on population pharmacokinetic analysis, the apparent volume of distribution of niraparib and abiraterone were 1 117 L and 25 774 L, respectively, indicative of extensive extravascular distribution.

Niraparib
Niraparib was moderately protein-bound in human plasma (83.0%), mainly with serum albumin.

Abiraterone acetate
The plasma protein binding of 14C-abiraterone in human plasma is 99.8%.
Biotransformation
Niraparib
Niraparib is metabolised primarily by carboxylesterases (CEs) to form a major inactive metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major circulating metabolites. The potential to inhibit CYP3A4 at the intestinal level has not been established at relevant niraparib concentrations. Niraparib weakly induces CYP1A2 at high concentrations in vitro.

Abiraterone acetate
Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed by CEs to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. Abiraterone is a substrate of CYP3A4 and sulfotransferase 2A1 (SULT2A1). The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, two main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.
Abiraterone is an inhibitor of the hepatic drug metabolising enzymes CYP2D6 and CYP2C8 (see section 4.5).

Elimination
Akeega
The mean t½ of niraparib and abiraterone when given in combination were approximately 62 hours and 20 hours, respectively, and apparent CL/F of niraparib and abiraterone were 16.7 L/h and 1673 L/h,
respectively based on the population pharmacokinetic analysis in subjects with mCRPC.

Niraparib
Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following an oral administration of a single 300 mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) of the dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accounted for 47.5% (range 33.4% to 60.2%) and in the faeces for 38.8% (range 28.3% to 47.0%) of the dose. In pooled samples collected over six days, 40.0% of the dose was recovered in the urine primarily as metabolites and 31.6% of the dose was recovered in the faeces primarily as unchanged niraparib. The metabolite M1 is a substrate of Multidrug And Toxin Extrusion (MATE) 1 and 2.

Abiraterone acetate
Following oral administration of 14C-abiraterone acetate 1 000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).


Akeega-50/500_mg_100/500_mg_Film Coated Tablets_PI_09_2024
Effects of niraparib or abiraterone on transporters
Niraparib inhibits P-gp weakly with an IC50=161 μM. Niraparib is an inhibitor of BCRP, Organic Cation Transporter 1 (OCT1), MATE-1 and 2 with IC50 values of 5.8 μM, 34.4 μM, 0.18 μM and ≤ 0.14 μM, respectively. The major metabolites of abiraterone, abiraterone sulphate and N-oxide abiraterone sulphate, were shown to inhibit the hepatic uptake transporter Organic Anion Transport Polypeptide 1B1 (OATP1B1) and as a consequence, the plasma exposures of medicinal products eliminated by OATP1B1 may increase. There are no clinical data available to confirm transporter OATP1B1 based interaction.

Special populations
Hepatic impairment
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib/AA in combination, mild hepatic impairment (NCI- ODWG criteria, n=231) did not affect the exposure of niraparib.

In a clinical study of cancer patients using NCI-ODWG criteria to classify the degree of hepatic impairment, niraparib AUCinf in patients with moderate hepatic impairment (n=8) was 1.56 (90% CI: 1.06 to 2.30) times the niraparib AUCinf in patients with normal hepatic function (n=9) following administration of a single 300 mg dose.

The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects. Systemic exposure to abiraterone after a single oral 1 000 mg dose increased by approximately 1.11-fold and 3.6-fold in subjects with mild and moderate pre-existing hepatic impairment, respectively.

In another study, the pharmacokinetics of abiraterone were examined in subjects with pre-existing severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The AUC of abiraterone increased by approximately 7-fold and the fraction of free drug increased by 1.8-fold in subjects with severe hepatic impairment compared to subjects with normal hepatic function. There is no clinical experience using Akeega in patients with moderate and severe hepatic impairment (see section 4.2).

Renal impairment
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib/AA in combination, patients with mild (creatinine clearance 60-90 mL/min, n=337) and moderate (creatinine clearance 30-60 mL/min, n=114) renal impairment had mildly reduced niraparib clearance compared to individuals with normal renal function (up to 13% higher exposure in mild and 13-40% higher exposure in moderate renal impairment).

The pharmacokinetics of abiraterone was compared in patients with end-stage renal disease on a stable haemodialysis schedule (n=8) versus matched control subjects with normal renal function (n=8).
Systemic exposure to abiraterone after a single oral 1 000 mg dose did not increase in subjects with end-stage renal disease on dialysis. There is no clinical experience using Akeega in patients with severe renal impairment (see section 4.2).

Weight, age and race
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib or abiraterone acetate alone or in combination:
•     Body weight did not have a clinically meaningful influence on the exposure of niraparib (body weight range: 43.3-165 kg) and abiraterone (body weight range: 56.0-135 kg).
•     Age had no significant impact on the pharmacokinetics of niraparib (age range 45-90 years) and abiraterone (age range 19-85 years).
•     There is insufficient data to conclude on the impact of race on the pharmacokinetics of niraparib and abiraterone.

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Paediatric population
No studies have been conducted to investigate the pharmacokinetics of Akeega in paediatric patients.