Mechanism Of Action
SIGNIFOR is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTRs). Five human somatostatin receptor subtypes are known: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing's disease patients frequently over-express SSTR5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.
The binding affinities of endogenous somatostatin and pasireotide are shown in Table 2.
Table 2: Binding affinities
of somatostatin (SRIF-14) and pasireotide to the five human somatostatin
receptor subtypes (SSTR1-5)
|Somatostatin (SRIF-14)||0.93 ± 0.12||0.15 ± 0.02||0.56 ± 0.17||1.5 ± 0.4||0.29 ± 0.04|
|Pasireotide||9.3 ± 0.1||1.0 ± 0.1||1.5 ± 0.3||> 100||0.16 ± 0.01|
|Results are the mean±SEM of IC50 values expressed as nmol/l|
In a randomized, double-blind mechanism study conducted in healthy volunteers, the development of hyperglycemia with pasireotide at doses of 0.6 mg b.i.d. and 0.9 mg b.i.d. 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]). [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
QTcI interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide doses of 0.6 mg b.i.d. and 1.95 mg b.i.d. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg bid, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg b.i.d. The supra-therapeutic dose (1.95 mg b.i.d) produced mean steady-state Cmax values 3.3-fold the mean Cmax for the 0.6 mg b.i.d dose in the study.
In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a dose range from 0.0025 to 1.5 mg. In Cushing's disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3 to 1.2 mg.
Absorption and Distribution
In healthy volunteers, pasireotide peak plasma concentration is reached within Tmax 0.25-0.5 hour. Cmax and AUC are dose-proportional following administration of single and multiple doses.
No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR is administered via a parenteral route.
In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F > 100 L). Distribution between blood 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.
Pasireotide has low passive permeability and is likely to be a substrate of P-gp (P-glycoprotein), but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition (e.g., verapamil) did not affect the rate or extent of pasireotide availability. Pasireotide is not a substrate of efflux transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic cation transporter 1), or influx transporters OATP (organic anion-transporting polypeptide) 1B1, 1B3, or 2B1.
Metabolism and Excretion
Pasireotide was shown to be metabolically stable in human liver and kidney microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine, and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes.
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 radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine.
The clearance (CL/F) of pasireotide in healthy volunteers and Cushing's disease patients is ~7.6 L/h and ~3.8 L/h, respectively.
Following multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once a day in healthy volunteers, and 0.3 mg to 1.2 mg twice a day in Cushing's disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 0.2 and 0.6 mg once a day doses).
Population PK analyses of SIGNIFOR indicate that race, body weight, age, and gender do not have a clinically relevant influence on PK parameters. No dose adjustment is required for demographics.
In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUCinf was increased by 12%, 56% and 42% and Cmax increased by 3%, 46% and 33%, respectively, in the mild, moderate and severe hepatic impairment groups [see Use In Specific Populations and DOSAGE AND ADMINISTRATION].
No studies have been performed in pediatric patients [see Use In Specific Populations].
No clinical pharmacology studies have been performed in geriatric patients.
Clinical pharmacology studies have not been performed in patients with impaired renal function. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function is not expected to significantly impact the circulating levels of pasireotide [see Use in Specific Populations].
Drug Interaction Studies
There was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide.
A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over a 6-month treatment period in Cushing's disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery.
Patients with a baseline 24-hour urine free cortisol (UFC) > 1.5 x upper limit of normal (ULN) were randomized to receive a SIGNIFOR dosage of either 0.6 mg subcutaneous b.i.d. or 0.9 mg subcutaneous b.i.d. After three months of treatment, patients with a mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg b.i.d. After the initial six months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg b.i.d. at any time during the study for intolerability.
A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing's disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed six months of treatment.
The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after six months of treatment and did not dose increase during this period.
24-Hour Urinary Free Cortisol Results
At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg b.i.d. and 0.9 mg b.i.d. groups, respectively (Table 3). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg bid and 41% in the 0.9 mg bid groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3.
Table 3: 24-Hour Urinary
Free Cortisol (UFC) Study Results at Month 6 in Patients with Cushing’s Disease
|SIGNIFOR 0.6 mg b.i.d.
|SIGNIFOR 0.9 mg b.i.d.
|% (95% CI)||15% (7%, 22%)||26% (17%, 36%)|
|UFC Levels (nmol/24hr)||N=78||N=72|
|Mean (SD)||868 (764)||750 (930)|
|% Change from baseline|
|Mean (95% CI)||-22% (-44%, +1%)||-42% (-50%, -33%)|
SIGNIFOR resulted in a decrease in the mean 24-hour UFC after 1 month of treatment (Figure 1). For patients (n=78) who stayed in the trial, similar UFC lowering was observed at Month 12.
Figure 1 : Mean (±SE)
Urinary Free Cortisol (nmol/24h) at time points up to Month 6 by randomized
Note: Only patients who completed 6 months of treatment are included in this analysis (n=110). The reference line is the upper limit of normal for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed.
Decreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any antihypertensive medication. However, due to the fact that the study allowed initiation of antihypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of antihypertensive medication adjustments cannot be clearly established.
The mean decreases from baseline at Month 6 for weight, body mass index and waist circumference were 4.4 kg, 1.6 kg/m² and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushing's disease manifestations but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR.
Last reviewed on RxList: 4/7/2015
This monograph has been modified to include the generic and brand name in many instances.
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