Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and analogues, ATC code: H01CB05

Mechanism of action

Pasireotide is a cyclohexapeptide, injectable somatostatin analogue. Like the natural peptide hormones somatostatin-14 and somatostatin-28 (also known as somatotropin release inhibiting factor [SRIF]) and other somatostatin analogues, pasireotide exerts its pharmacological activity via binding to somatostatin receptors. Five human somatostatin receptor subtypes are known: hsst1, 2, 3, 4, and 5.
These receptor subtypes are expressed in different tissues under normal physiological conditions.
Somatostatin analogues bind to hsst receptors with different potencies (see Table 2). Pasireotide binds with high affinity to four of the five hssts.

Table 2      Binding affinities of somatostatin (SRIF-14), pasireotide, octreotide and lanreotide to the five human somatostatin receptor subtypes (hsst1-5)
Compound                 hsst1            hsst2             hsst3          hsst4        hsst5 Somatostatin           0.93±0.12        0.15±0.02         0.56±0.17      1.5±0.4      0.29±0.04 (SRIF-14)
Pasireotide             9.3±0.1          1.0±0.1           1.5±0.3        >1,000      0.16±0.01 Octreotide              280±80          0.38±0.08          7.1±1.4        >1,000       6.3±1.0 Lanreotide              180±20          0.54±0.08            14±9        230±40          17±5 Results are the mean±SEM of IC50 values expressed as nmol/l.

Pharmacodynamic effects

Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in which hormones are excessively secreted, including GH in acromegaly and ACTH in Cushing’s disease.

In vitro studies have shown that corticotroph tumour cells from Cushing’s disease patients display a high expression of hsst5, whereas the other receptor subtypes either are not expressed or are expressed at lower levels. Pasireotide binds and activates four of the five hssts, especially hsst5, in corticotrophs of ACTH producing adenomas, resulting in inhibition of ACTH secretion.

Due to its broad binding profile to somatostatin receptors, pasireotide has the potential to stimulate both hsst2 and hsst5 subtype receptors relevant for inhibition of GH and IGF-1 secretion and therefore to be effective for the treatment of acromegaly.

Glucose metabolism
In a randomised double-blinded mechanism study conducted in healthy volunteers, the development of hyperglycaemia with pasireotide administered as pasireotide subcutaneous use at doses of 0.6 and 0.9 mg twice a day was related to significant decreases in insulin secretion as well as incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). Pasireotide did not affect insulin sensitivity.

Clinical efficacy and safety

The efficacy of pasireotide intramuscular use has been demonstrated in two phase III, multicentre studies in acromegaly patients and in one phase III, multicentre study in Cushing’s disease patients.

Acromegaly study C2402, inadequately controlled patients
Study C2402 was a phase III, multicentre, randomised, parallel-group, three-arm study of double-blind pasireotide intramuscular use 40 mg and 60 mg versus open-label octreotide intramuscular use 30 mg or lanreotide deep subcutaneous injection 120 mg in patients with inadequately controlled acromegaly.
A total of 198 patients were randomised to receive pasireotide intramuscular use 40 mg (n=65), pasireotide intramuscular use 60 mg (n=65) or active control (n=68). 192 patients were treated. A total of 181 patients completed the core phase (24 weeks) of the study.

Inadequately controlled patients in study C2402 are defined as patients with a mean GH concentration of a 5-point profile over a 2-hour period >2.5 μg/l and sex- and age-adjusted IGF-1 >1.3 × ULN.
Patients had to be treated with maximum indicated doses of octreotide intramuscular use (30 mg) or lanreotide deep subcutaneous injection (120 mg) for at least 6 months prior to randomisation.
Three-quarters of patients had previously been treated with octreotide intramuscular use and a quarter with lanreotide deep subcutaneous injection. Nearly half of the patients had additional prior medical treatment for acromegaly other than somatostatin analogues. Two-thirds of all patients had undergone prior surgery. Baseline mean GH was 17.6 µg/l, 12.1 µg/l and 9.5 µg/l, in the 40 mg, 60 mg and active control groups, respectively. IGF-1 mean values at baseline were 2.6, 2.8 and 2.9 x ULN, respectively.

The primary efficacy endpoint was to compare the proportion of patients achieving biochemical control (defined as mean GH levels <2.5 μg/l and normalisation of sex- and age-adjusted IGF-1) at week 24 with pasireotide intramuscular use 40 mg or 60 mg versus continued treatment with active control (octreotide intramuscular use 30 mg or lanreotide deep subcutaneous injection 120 mg), separately. The study met its primary efficacy endpoint for both pasireotide intramuscular use doses.
The proportion of patients achieving biochemical control was 15.4% (p-value = 0.0006) and 20.0% (p-value <0.0001) for pasireotide intramuscular use 40 mg and 60 mg, respectively at 24 weeks compared with zero in the active control arm (Table 3).



Table 3     Key results at week 24 (Study C2402)

Signifor LAR           Signifor LAR          Active control intramuscular use      intramuscular use     N=68
40 mg                  60 mg                 n (%)
N=65                   N=65 n (%), p value         n (%), p value
GH<2.5 μg/l and normalised            10 (15.4%), p=0.0006   13 (20.0%),           0 (0%) IGF-1*                                                       p<0.0001 Normalisation of IGF-1               16 (24.6%), p<0.0001 17 (26.2%),              0 (0%) p<0.0001
GH<2.5 μg/l                          23 (35.4%)              28 (43.1%)            9 (13.2%) * Primary endpoint (patients with IGF-1< lower limit of normal (LLN) were not considered “responders”).

In patients treated with pasireotide intramuscular use in whom reductions in GH and IGF-1 levels were observed, these changes occurred during the first 3 months of treatment and were maintained up to week 24.

The proportion of patients with a reduction or no change in pituitary tumour volume at week 24 was 81.0% and 70.3% on pasireotide intramuscular use 40 and 60 mg, and 50.0% on active control.
Furthermore, a higher proportion of patients on pasireotide intramuscular use (18.5% and 10.8% for 40 mg and 60 mg, respectively) than active comparator (1.5%) achieved a reduction in tumour volume of at least 25%.

Health-related quality of life measured by AcroQol indicated statistically significant improvements from baseline to week 24 in the Physical, Psychological-Appearance and Global scores for the 60 mg group and the Physical sub-score for the 40mg group. Changes for the octreotide intramuscular use or lanreotide deep subcutaneous injection group were not statistically significant. The improvement observed up to week 24 between the treatment groups was also not statistically significant.

Acromegaly study C2305 patients who had no prior medical treatment
A phase III multicentre, randomised, blinded study was conducted to assess the safety and efficacy of pasireotide intramuscular use versus octreotide intramuscular use in medically naïve patients with active acromegaly. A total of 358 patients were randomised and treated. Patients were randomised in a 1:1 ratio to one of two treatment groups in each of the following two strata: 1) patients who had undergone one or more pituitary surgeries but had not been treated medically or 2) de novo patients presenting a visible pituitary adenoma on MRI who had refused pituitary surgery or for whom pituitary surgery was contraindicated.

The two treatment groups were well balanced in terms of baseline demographics and disease characteristics. 59.7% and 56% of patients in the pasireotide intramuscular use and octreotide intramuscular use treatment groups, respectively, were patients without previous pituitary surgery (de novo).

The starting dose was 40 mg for pasireotide intramuscular use and 20 mg for octreotide intramuscular use. Dose increase for efficacy was allowed at the discretion of the investigators after three and six months of treatment if biochemical parameters showed a mean GH ≥2.5 µg/l and/or IGF-1 >ULN (age and sex related). Maximum allowed dose was 60 mg for pasireotide intramuscular use and 30 mg for octreotide intramuscular use.

The primary efficacy endpoint was the proportion of patients with a reduction of mean GH level to <2.5 μg/l and the normalisation of IGF-1 to within normal limits (age and sex related) at month 12.
The primary efficacy endpoint was met; the percentage of patients achieving biochemical control was 31.3% and 19.2% for pasireotide intramuscular use and octreotide intramuscular use, respectively, 
demonstrating a statistically significant superior result favouring pasireotide intramuscular use (p-value = 0.007) (Table 4).

Table 4      Key results at month 12 - phase III study in acromegaly patients 
Pasireotide          Octreotide          p-value intramuscular use intramuscular use n (%)                n (%)
N=176                N=182
GH <2.5 μg/l and normalised IGF-1*              31.3%                19.2%             p=0.007 GH <2.5 μg/l and IGF-1 ≤ULN                     35.8%                20.9%                - Normalised IGF-1                                38.6%                23.6%             p=0.002 GH <2.5 μg/l                                    48.3%                51.6%             p=0.536 * Primary endpoint (patients with IGF-1 1.5xULN had their doses increased in a blinded manner from 10 mg to 30 mg, or from 30 mg to 40 mg, provided there were no tolerability concerns. Additional dose adjustments (up to a maximum of 40 mg) were allowed at months 7 and 9 of the core phase. The primary efficacy end point was the proportion of patients in each arm who achieved mean 24-hour UFC levels ≤ULN after 7 months of treatment, regardless of prior dose increase. Secondary end points included changes from baseline in: 24-hour UFC, plasma ACTH, serum cortisol levels, and clinical signs and symptoms of Cushing’s disease. All analyses were conducted based on the randomised dose groups.

Results
The study met the primary efficacy objective for both dose groups (lower bound of the 95% CI for the response rate of each treatment arm >15%). At month 7, a mUFC response was achieved in 41.9% and 40.8% of patients randomised to starting doses of 10 mg and 30 mg, respectively. The proportion of patients who either attained mUFC ≤ULN or a mUFC reduction from baseline of at least 50% was 50.0% in the 10 mg dose group and 56.6% in the 30 mg dose groups (Table 5).

In both dose groups, Signifor resulted in a decrease in mean UFC after 1 month of treatment, and this was maintained over time. Decreases were also demonstrated by the overall percentage change from baseline in mean and median mUFC levels at month 7 and 12. Reductions in serum cortisol and plasma ACTH levels were also observed at month 7 and 12 for each dose group.

Table 5     Key results - phase III study in Cushing’s disease patients (intramuscular formulation)

Pasireotide 10 mg       Pasireotide 30 mg
N=74                    N=76
Percentage of patients with: mUFC ≤ULN at Month 7 (95% CI) *                 41.9 (30.5, 53.9)        40.8 (29.7, 52.7) mUFC ≤ULN and no prior dose increase            28.4 (18.5, 40.1)        31.6 (21.4, 43.3) at Month 7 (95% CI) mUFC ≤ULN or ≥50% decrease from                 50.0 (38.1, 61.9)        56.6 (44.7, 67.9) baseline at month 7 (95% CI)
Median (min, max) % mUFC change from                -47.9 (-94.2, 651.1)     -48.5 (-99.7, 181.7) baseline at month 7
Median (min, max) % mUFC change from                -52.5 (-96.9, 332.8)     -51.9 (-98.7, 422.3) baseline at month 12
* Primary endpoint using LOCF (last observation carried forward) mUFC: mean urinary free cortisol; ULN: upper limit of normal; CI: confidence interval 

Decreases in systolic and diastolic blood pressure and in body weight were observed in both dose groups at month 7. Overall reductions in these parameters tended to be greater in patients that were mUFC responders. Similar trends were observed at month 12.

At month 7, most patients demonstrated either improvement in or stable signs of Cushing’s disease such as hirsuitism, striae, bruising and muscle strength. Facial rubor improved in 43.5% (47/108) of patients, and more than a third of patients demonstrated improvement in supraclavicular fat pad (34.3%) and dorsal fat pad (34.6%). Similar results were also seen at month 12.

Health-related quality of life was assessed by a disease-specific patient-reported outcome measure (CushingQoL) and a generic quality of life measure (SF-12v2 General Health Survey). Improvements were observed in both dose groups for CushingQoL and the Mental Component Summary (MCS) of SF-12v2, but not for the Physical Component Summary (PCS) of SF-12v2.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Pasireotide for intramuscular use is formulated as microspheres for long-acting release. After a single injection, the plasma pasireotide concentration shows an initial burst release on the injection day, followed by a dip from day 2 to day 7, then a slow increase to maximum concentration around day 21, and a slow declining phase over the next weeks, concomitant with the terminal degradation phase of the polymer matrix of the dosage form.

Absorption

The relative bioavailability of pasireotide intramuscular use over pasireotide subcutaneous use is complete. No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans.

Distribution

In healthy volunteers, pasireotide intramuscular use is widely distributed with large apparent volume of distribution (Vz/F >100 litres). Distribution between blood cells and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.

Based on in vitro data pasireotide appears to be a substrate of efflux transporter P-gp (P-glycoprotein).
Based on in vitro data pasireotide is not a substrate of the efflux transporter BCRP (breast cancer resistance protein) nor of the influx transporters OCT1 (organic cation transporter 1), OATP (organic anion-transporting polypeptide) 1B1, 1B3 or 2B1. At therapeutic dose levels pasireotide is also not an inhibitor of UGT1A1, OATP1B1 or 1B3, OAT1 or OAT3, OCT1 or OCT2, P-gp, BCRP, MRP2 and BSEP.

Biotransformation

Pasireotide is metabolically highly stable and in vitro data show that pasireotide is not a substrate, inhibitor or inducer of CYP450. In healthy volunteers, pasireotide is predominantly found in unchanged form in plasma, urine and faeces.

Elimination

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion), with a small contribution of the renal route. In a human ADME study 55.9±6.63% of the radioactive pasireotide subcutaneous dose was recovered over the first 10 days after administration, including 48.3±8.16% of the radioactivity in faeces and 7.63±2.03% in urine.

The apparent clearance (CL/F) of pasireotide intramuscular use in healthy volunteers is on average 
4.5-8.5 litres/h. Based on population pharmacokinetic (PK) analyses, the estimated CL/F was approximately 4.8 to 6.5 litres/h for typical Cushing’s disease patients, and approximately 5.6 to 8.2 litres/h for typical acromegaly patients.

Linearity and time dependency

Pharmacokinetic steady state for pasireotide intramuscular use is achieved after three months.
Following multiple monthly doses, pasireotide intramuscular use demonstrates approximately dose-proportional pharmacokinetic exposures in the dose range of 10 mg to 60 mg every 4 weeks.

Special populations

Paediatric population
No studies have been performed in paediatric patients.
Patients with renal impairment
Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical study with single subcutaneous dose administration of 900 μg pasireotide in subjects with impaired renal function, renal impairment of mild, moderate or severe degree, or end stage renal disease (ESRD) did not have a significant impact on total pasireotide plasma exposure. The unbound plasma pasireotide exposure (AUCinf,u) was increased in subjects with renal impairment (mild: 33%; moderate: 25%, severe: 99%, ESRD: 143%) compared to control subjects.

Patients with hepatic impairment
No clinical studies in subjects with liver impairment have been performed with pasireotide intramuscular use. In a clinical study of a single subcutaneous dose of pasireotide in subjects with impaired hepatic function, statistically significant differences were found in subjects with moderate and severe hepatic impairment (Child-Pugh B and C). In subjects with moderate and severe hepatic impairment, AUCinf was increased 60% and 79%, Cmax was increased 67% and 69%, and CL/F was decreased 37% and 44%, respectively.

Elderly patients (≥65 years)
Age is not a significant covariate in the population pharmacokinetic analysis of patients 
Demographics
Population PK analyses of pasireotide intramuscular use suggest that race does not influence PK parameters. PK exposures had a slight correlation with body weight in the study with medical treatment naïve patients, but not in the study with inadequately controlled patients. Female acromegaly patients had a higher exposure of 32% and 51% compared to male patients in studies with medical treatment naïve patients and inadequately controlled patients, respectively; these differences in exposure were not clinically relevant based on efficacy and safety data.