Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08

Mechanism of action
Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

Pharmacodynamic effects
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone.
The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase.
The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.
Aclasta treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks.
Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.

Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT) The efficacy and safety of Aclasta 5 mg once a year for 3 consecutive years were demonstrated in post- menopausal women (7,736 women aged 65–89 years) with either: a femoral neck bone mineral density (BMD) with a T-score ≤ –1.5 and at least two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD T-score ≤ –2.5 with or without evidence of existing vertebral fracture(s). 85% of patients were bisphosphonate-naïve. Women who were evaluated for the incidence of vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for women contributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapy included: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded other bisphosphonates. All women received 1,000 to 1,500 mg elemental calcium and 400 to 1,200 IU of vitamin D supplements daily.

Effect on morphometric vertebral fractures
Aclasta significantly decreased the incidence of one or more new vertebral fractures over three years and as early as the one year timepoint (see Table 3).

Table 3 Summary of vertebral fracture efficacy at 12, 24 and 36 months 

ACL API MAY21 V13                             Page 10 of 17                  EU SmPC Mar2021, NZ DS AUG 2020 Outcome                        Aclasta      Placebo       Absolute reduction in      Relative reduction in (%)          (%)           fracture incidence %       fracture incidence % (CI)                       (CI)
At least one new vertebral     1.5          3.7           2.2 (1.4, 3.1)             60 (43, 72)** fracture (0–1 year)
At least one new vertebral     2.2          7.7           5.5 (4.4, 6.6)             71 (62, 78)** fracture (0–2 year)
At least one new vertebral     3.3          10.9          7.6 (6.3, 9.0)             70 (62, 76)** fracture (0–3 year)
** p <0.0001

Aclasta-treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebral fractures compared to placebo patients (p<0.0001).

Effect on hip fractures
Aclasta demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hip fractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for Aclasta-treated patients compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-naïve patients and 42% in patients allowed to take concomitant osteoporosis therapy.

Effect on all clinical fractures
All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 4.

Table 4      Between treatment comparisons of the incidence of key clinical fracture variables over 3 years
Outcome                               Aclasta        Placebo        Absolute            Relative risk (N=3,875)      (N=3,861)      reduction in        reduction in event rate     event rate     fracture event rate fracture
(%)            (%)            %                   incidence %
(CI)                (CI)
Any clinical fracture (1)             8.4            12.8           4.4 (3.0, 5.8)      33 (23, 42)** Clinical vertebral fracture (2)       0.5            2.6            2.1 (1.5, 2.7)      77 (63, 86)** Non-vertebral fracture (1)           8.0            10.7           2.7 (1.4, 4.0)      25 (13, 36)* *p-value <0.001, **p-value <0.0001
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures 
Effect on bone mineral density (BMD)
Aclasta significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment with placebo at all timepoints (6, 12, 24 and 36 months). Treatment with Aclasta resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal radius over 3 years as compared to placebo.

Bone histology
Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 post-menopausal patients with osteoporosis treated with Aclasta (N=82) or placebo (N=70).
Histomorphometric analysis showed a 63% reduction in bone turnover. In patients treated with Aclasta, no osteomalacia, marrow fibrosis or woven bone formation was detected. Tetracycline label was detectable in all but one of 82 biopsies obtained from patients on Aclasta. Microcomputed tomography (μCT) analysis demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients treated with Aclasta compared to placebo.

Bone turnover markers

ACL API MAY21 V13                             Page 11 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum beta-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517 to 1,246 patients at periodic intervals throughout the study. Treatment with a 5 mg annual dose of Aclasta significantly reduced BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 36 months. P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 52% below baseline levels at 36 months. B-CTx was significantly reduced by 61% below baseline levels at 12 months and was sustained at 55% below baseline levels at 36 months.
During this entire time period bone turnover markers were within the pre-menopausal range at the end of each year. Repeat dosing did not lead to further reduction of bone turnover markers.

Effect on height
In the three-year osteoporosis study standing height was measured annually using a stadiometer. The Aclasta group revealed approximately 2.5 mm less height loss compared to placebo (95% CI: 1.6 mm, 3.5 mm) [p<0.0001].

Days of disability
Aclasta significantly reduced the mean days of limited activity and the days of bed rest due to back pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to placebo (all p<0.01).

Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fracture after a recent hip fracture (RFT)
The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low-trauma hip fracture who were followed for an average of 2 years on study treatment (Aclasta).
Approximately 42% of patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral neck BMD T-score above -2.5. Aclasta was administered once a year, until at least 211 patients in the study population had confirmed clinical fractures. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or by intramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation per day. Ninety-five percent of the patients received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was approximately six weeks after the hip fracture repair. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.

Effect on all clinical fractures
The incidence rates of key clinical fracture variables are presented in Table 5.

Table 5      Between treatment comparisons of the incidence of key clinical fracture variables 
Outcome                               Aclasta        Placebo       Absolute reduction     Relative risk (N=1,065)      (N=1,062)     in fracture event      reduction in event rate     event rate    rate %                 fracture incidence (%)            (%)           (CI)                   % (CI)
Any clinical fracture (1)             8.6            13.9          5.3 (2.3, 8.3)          35 (16, 50)** Clinical vertebral fracture (2)       1.7            3.8           2.1 (0.5, 3.7)          46 (8, 68)* Non-vertebral fracture (1)            7.6            10.7          3.1 (0.3, 5.9)          27 (2, 45)* *p-value <0.05, **p-value <0.01
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures 
The study was not designed to measure significant differences in hip fracture, but a trend was seen towards reduction in new hip fractures.

All cause mortality was 10% (101 patients) in the Aclasta-treated group compared to 13% (141 patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause mortality (p=0.01).
ACL API MAY21 V13                             Page 12 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 The incidence of delayed hip fracture healing was comparable between Aclasta (34 [3.2%]) and placebo (29 [2.7%]).

Effect on bone mineral density (BMD)
In the HORIZON-RFT study Aclasta treatment significantly increased BMD at the total hip and femoral neck relative to treatment with placebo at all timepoints. Treatment with Aclasta resulted in an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months as compared to placebo.

Clinical efficacy in men
In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD assessed at 24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was observed for patients treated with Aclasta as compared to the effects observed in post-menopausal women in the HORIZON-PFT study. The study was not powered to show a reduction in clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with Aclasta versus 8.7% for placebo.
In another study in men (study CZOL446M2308) an annual infusion of Aclasta was non-inferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline.

Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy The efficacy and safety of Aclasta in the treatment and prevention of osteoporosis associated with long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-blind, stratified, active- controlled study of 833 men and women aged 18-85 years (mean age for men 56.4 years; for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified with respect to duration of glucocorticoid use prior to randomisation (≤ 3 months versus > 3 months).
The duration of the trial was one year. Patients were randomised to either Aclasta 5 mg single infusion or to oral risedronate 5 mg daily for one year. All participants received 1,000 mg elemental calcium plus 400 to 1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if non-inferiority to risedronate was shown sequentially with respect to the percentage change in lumbar spine BMD at 12 months relative to baseline in the treatment and prevention subpopulations, respectively. The majority of patients continued to receive glucocorticoids for the one year duration of the trial.

Effect on bone mineral density (BMD)
The increases in BMD were significantly greater in the Aclasta-treated group at the lumbar spine and femoral neck at 12 months compared to risedronate (all p<0.03). In the subpopulation of patients receiving glucocorticoids for more than 3 months prior to randomisation, Aclasta increased lumbar spine BMD by 4.06% versus 2.71% for risedronate (mean difference: 1.36% ; p<0.001). In the subpopulation of patients that had received glucocorticoids for 3 months or less prior to randomisation, Aclasta increased lumbar spine BMD by 2.60% versus 0.64% for risedronate (mean difference: 1.96% ; p<0.001). The study was not powered to show a reduction in clinical fractures compared to risedronate.
The incidence of fractures was 8 for Aclasta-treated patients versus 7 for risedronate-treated patients (p=0.8055).

Clinical efficacy in the treatment of Paget’s disease of the bone
Aclasta was studied in male and female patients aged above 30 years with primarily mild to moderate Paget’s disease of the bone (median serum alkaline phosphatase level 2.6–3.0 times the upper limit of the age- specific normal reference range at the time of study entry) confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months was demonstrated in two 6-month comparative trials. After 6 months, Aclasta showed 96%
(169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation rates compared to 74% (127/171) and 58% (99/171) for risedronate (all p<0.001).

In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were observed over 6 months for Aclasta and risedronate.

Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period. Of the 153 Aclasta-treated patients and 115 risedronate-treated patients who entered an extended observation study, after a mean duration of follow-up of 3.8 years from time of dosing, the ACL API MAY21 V13                             Page 13 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 proportion of patients ending the Extended Observation Period due to the need for re-treatment (clinical judgment) was higher for risedronate (48 patients, or 41.7%) compared with zoledronic acid (11 patients, or 7.2%). The mean time of ending the Extended Observation Period due to the need for Paget’s re-treatment from the initial dose was longer for zoledronic acid (7.7 years) than for risedronate (5.1 years).

Six patients who achieved therapeutic response 6 months after treatment with Aclasta and later experienced disease relapse during the extended follow-up period were re-treated with Aclasta after a mean time of 6.5 years from initial treatment to re-treatment. Five of the 6 patients had SAP within the normal range at month 6 (Last Observation Carried Forward, LOCF).

Bone histology was evaluated in 7 patients with Paget’s disease 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralisation defects. These results were consistent with biochemical marker evidence of normalisation of bone turnover.

Prevention of Postmenopausal Osteoporosis
The efficacy and safety of Aclasta in the prevention of osteoporosis in postmenopausal women was assessed in a 2-year randomised, multi-centre, double-blind, placebo-controlled study of 581 postmenopausal women aged >45 years, who were stratified by years since menopause: Stratum I women <5 years from menopause (n = 224); Stratum II women >5 years from menopause (n= 357). Patients within Stratum I and II were randomised to one of three treatment groups: Aclasta was given annually: at randomisation and Month 12 (n= 77) in Stratum I and (n=121) in Stratum II. Aclasta given at randomisation and placebo at Month 12 (n=70) in Stratum I and (n=111) in Stratum II. Placebo was given at randomisation and Month 12 (n=202). Aclasta was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1,200 mg elemental calcium plus 400 to 800 IU vitamin D supplementation per day. The primary efficacy variable was the percent change of BMD at 24 Months relative to baseline.

Effect on bone mineral density
Aclasta significantly increased lumbar spine BMD relative to placebo at Month 24. Treatment with Aclasta given annually resulted in 6.9% increase in BMD in Stratum I patients and 6.2% in Stratum II patients (both p<0.0001).
Also, Aclasta given at randomisation resulted in 6.3% increase in BMD in Stratum I patients and 5.4% in Stratum II patients (both p<0.0001).
Aclasta administered annually and as a single dose significantly increased total hip BMD relative to placebo at Month 24 across both strata (all p <0.0001). Treatment with Aclasta given annually resulted in 4.8% increase in BMD in Stratum I patients and 4.1% in Stratum II patients relative to placebo. Treatment with a single dose of Aclasta resulted in 4.7% increase in BMD in Stratum I patients and 3.2% in Stratum II patients relative to placebo.

Bone turnover markers
The effect of Aclasta treatment on markers of bone resorption b-CTx and bone formation BSAP, P1NP was evaluated in 571 patients stratified by duration from menopause at periodic intervals. Treatment with Aclasta results in a significantly greater reduction in bone turnover markers compared to placebo, and with the two annual Aclasta doses there was a significantly greater reduction compared to the single Aclasta dose. The two annual doses of Aclasta and the single Aclasta dose were associated with reductions in bone turnover markers to the premenopausal range with an approximate 55% and 44% reductions in b-CTx in postmenopausal women within 5 years of menopause, respectively, and approximately 59% and 46% reduction in b-CTx in postmenopausal women 5 years or more from menopause, respectively, over 24 months. The two annual doses of Aclasta and the single Aclasta dose were both associated with approximately 55% and 40% reductions in P1NP, in postmenopausal women within 5 years and 5 years or more from menopause, over 24 months.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients yielded the following pharmacokinetic data, which were found to be dose independent.


ACL API MAY21 V13                             Page 14 of 17                  EU SmPC Mar2021, NZ DS AUG 2020 Distribution
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak levels.

Elimination
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t½0.24 and t½β1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t½146 hours. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (α and β, with t½ values above) presumably represent rapid uptake into bone and excretion via the kidneys.

Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones is very long. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 l/h, independent of dose, and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively.
Increasing the infusion time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.

Pharmacokinetic/pharmacodynamic relationships
No interaction studies with other medicinal products have been performed with zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems.
Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-bound medicinal products are unlikely.

Special populations (see section 4.2)
Renal impairment
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ±33% of the creatinine clearance, which showed a mean of 84 ±29 ml/min (range 22 to 143 ml/min) in the 64 patients studied. Small observed increases in AUC(0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50–80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.