Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: all other therapeutic products, antidotes, ATC code: V03AB35 

Mechanism of action:
Sugammadex is a modified gamma cyclodextrin which is a Selective Relaxant Binding Agent.
It forms a complex with the neuromuscular blocking agents rocuronium or vecuronium in plasma and thereby reduces the amount of neuromuscular blocking agent available to bind to nicotinic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium or vecuronium.


Pharmacodynamic effects:
Sugammadex has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response studies of rocuronium induced blockade (0.6, 0.9, 1.0 and 1.2 mg/kg rocuronium bromide with and without maintenance doses) and vecuronium induced blockade (0.1 mg/kg vecuronium bromide with or without maintenance doses) at different time points/depths of blockade. In these studies a clear dose-response relationship was observed.


Clinical efficacy and safety:
Sugammadex can be administered at several time points after administration of rocuronium or vecuronium bromide:


Routine reversal   – deep neuromuscular blockade:
In a pivotal study patients were randomly assigned to the rocuronium or vecuronium group.
After the last dose of rocuronium or vecuronium, at 1-2 PTCs, 4 mg/kg sugammadex or 70 mcg/kg neostigmine was administered in a randomised order. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was: Table 3:Time (minutes) from administration of sugammadex or neostigmine at deep neuromuscular blockade (1-2 PTCs) after rocuronium or vecuronium to recovery of the T4/T1 ratio to 0.9
Neuromuscular blocking agent       Treatment regimen
Sugammadex (4 mg/kg)      Neostigmine (70 mcg/kg)
Rocuronium
N                                  37                        37
Median (minutes)                   2.7                       49.0
Range                              1.2-16.1                  13.3-145.7 Vecuronium
N                                  47                        36
Median (minutes)                   3.3                       49.9
Range                              1.4-68.4                  46.0-312.7 

Routine reversal   – moderate neuromuscular blockade:
In another pivotal study patients were randomly assigned to the rocuronium or vecuronium group. After the last dose of rocuronium or vecuronium, at the reappearance of T2, 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered in a randomised order. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was:


Table 4:Time (minutes) from administration of sugammadex or neostigmine at reappearance of T2 after rocuronium or vecuronium to recovery of the T4/T1 ratio to 0.9 Neuromuscular blocking agent       Treatment regimen
Sugammadex (2 mg/kg)      Neostigmine (50 mcg/kg)
Rocuronium
N                                  48                        48
Median (minutes)                   1.4                       17.6
Range                              0.9-5.4                   3.7-106.9 Vecuronium
N                                  48                        45
Median (minutes)                   2.1                       18.9
Range                              1.2-64.2                  2.9-76.2 

Reversal by sugammadex of the neuromuscular blockade induced by rocuronium was compared to the reversal by neostigmine of the neuromuscular blockade induced by cis- atracurium. At the reappearance of T2 a dose of 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered. Sugammadex provided faster reversal of neuromuscular blockade induced by rocuronium compared to neostigmine reversal of neuromuscular blockade induced by cis-atracurium:


Table 5: Time (minutes) from administration of sugammadex or neostigmine at reappearance of T2 after rocuronium or cis-atracurium to recovery of the T4/T1 ratio to 0.9
Neuromuscular blocking agent       Treatment regimen
Rocuronium and            Cis-atracurium and neostigmine sugammadex (2 mg/kg)      (50 mcg/kg)
N                                  34                        39
Median (minutes)                   1.9                       7.2
Range                              0.7-6.4                   4.2-28.2 For immediate reversal:
The time to recovery from succinylcholine-induced neuromuscular blockade (1 mg/kg) was compared with sugammadex (16 mg/kg, 3 minutes later) – induced recovery from rocuronium-induced neuromuscular blockade (1.2 mg/kg).


Table 6: Time (minutes) from administration of rocuronium and sugammadex or succinylcholine to recovery of the T1 10 %
Neuromuscular blocking agent        Treatment regimen
Rocuronium and               Succinylcholine (1 mg/kg) sugammadex
(16 mg/kg)
N                                   55                           55
Median (minutes)                    4.2                          7.1
Range                               3.5-7.7                      3.7-10.5 

In a pooled analysis the following recovery times for 16 mg/kg sugammadex after 1.2 mg/kg rocuronium bromide were reported:


Table 7: Time (minutes) from administration of sugammadex at 3 minutes after rocuronium to recovery of the T4/T1 ratio to 0.9, 0.8 or 0.7
T4/T1 to 0.9                  T4/T1 to 0.8               T4/T1 to 0.7 N                  65                            65                         65 Median             1.5                           1.3                        1.1 (minutes)
Range              0.5-14.3                      0.5-6.2                    0.5-3.3 

Renal impairment:
Two open label studies compared the efficacy and safety of sugammadex in surgical patients with and without severe renal impairment. In one study, sugammadex was administered following rocuronium induced blockade at 1-2 PTCs (4 mg/kg; N=68); in the other study, sugammadex was administered at reappearance of T2 (2 mg/kg; N=30). Recovery from blockade was modestly longer for patients with severe renal impairment relative to patients without renal impairment. No residual neuromuscular blockade or recurrence of neuromuscular blockade was reported for patients with severe renal impairment in these studies.

Morbidly obese patients:
A trial of 188 patients who were diagnosed as morbidly obese investigated the time to recovery from moderate or deep neuromuscular blockade induced by rocuronium or vecuronium. Patients received 2 mg/kg or 4 mg/kg sugammadex, as appropriate for level of block, dosed according to either actual body weight or ideal body weight in random, double- blinded fashion. Pooled across depth of block and neuromuscular blocking agent, the median time to recover to a train-of-four (TOF) ratio   ≥ 0.9 in patients dosed by actual body weight (1.8 minutes) was statistically significantly faster (p < 0.0001) compared to patients dosed by ideal body weight (3.3 minutes).


Patients with severe systemic disease:
A trial of 331 patients who were assessed as ASA Class 3 or 4 investigated the incidence of treatment-emergent arrhythmias (sinus bradycardia, sinus tachycardia, or other cardiac arrhythmias) after administration of sugammadex.
In patients receiving sugammadex (2 mg/kg, 4 mg/kg, or 16 mg/kg), the incidence of treatment-emergent arrhythmias was generally similar to neostigmine (50 µg/kg up to 5 mg maximum dose) + glycopyrrolate (10 µg/kg up to 1 mg maximum dose). The adverse reaction profile in ASA Class 3 and 4 patients was generally similar to that of adult patients in pooled Phase 1 to 3 studies; therefore, no dosage adjustment is necessary. See section 4.8.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
The sugammadex pharmacokinetic parameters were calculated from the total sum of non- complex-bound and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non- complex-bound and complex-bound sugammadex in anaesthetised subjects.


Distribution:
The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 litres in adult patients with normal renal function (based on conventional, non- compartmental pharmacokinetic analysis). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose.


Metabolism:
In preclinical and clinical studies no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination.


Elimination:
In adult anaesthetised patients with normal renal function the elimination half-life (t1/2) of sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min. A mass balance study demonstrated that > 90% of the dose was excreted within 24 hours. 96% of the dose was excreted in urine, of which at least 95% could be attributed to unchanged sugammadex. Excretion via faeces or expired air was less than 0.02% of the dose.
Administration of sugammadex to healthy volunteers resulted in increased renal elimination of rocuronium in complex.


Special populations:

Renal impairment and age:
In a pharmacokinetic study comparing patients with severe renal impairment to patients with normal renal function, sugammadex levels in plasma were similar during the first hour after dosing, and thereafter the levels decreased faster in the control group. Total exposure to sugammadex was prolonged, leading to 17-fold higher exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal insufficiency.
In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, sugammadex clearance progressively decreased and t1/2 was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal insufficiency.


Table 8: A summary of sugammadex pharmacokinetic parameters stratified by age and renal function is presented below:
Selected Patient Characteristics                          Mean Predicted PK Parameters (CV*%) 
Demographics                  Renal function            Clearance      Volume of distribution at   Elimination half- Creatinine clearance (mL/min)       (mL/min)           steady state (L)            life (hr) 

Adult              Normal                       100       88 (22)                  12                    2 (21) 
40 yrs             Impaired       Mild           50       51 (22)                  13                    4 (22)
75 kg                             Moderate       30       31 (23)                  14                    6 (23) 
Severe         10       9 (22)                   14                    19 (24) 

Elderly            Normal                        80       75 (23)                  12                    2 (21) 75 yrs             Impaired       Mild           50       51 (24)                  13                    3 (22) 75 kg                             Moderate       30       31 (23)                  14                    6 (23) Severe         10       9 (22)                   14                    19 (23) 

Adolescent         Normal                        95       77 (23)                   9                    2 (22) 15 yrs             Impaired       Mild           48       44 (23)                  10                    3 (22) 56 kg                             Moderate       29       27 (22)                  10                    5 (23) Severe         10       8 (21)                   11                    17 (23) 

Child              Normal                        51       37 (22)                   4                    2 (20) 7 yrs              Impaired       Mild           26       19 (22)                   4                    3 (22) 23 kg                             Moderate       15       11 (22)                   4                    5 (22)
Severe             5    3 (22)                   5                     20 (25) 

*CV=coefficient of variation

Gender:
No gender differences were observed.

Race:
In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data does not indicate differences in pharmacokinetic parameters in Black or African Americans.


Body weight:
Population pharmacokinetic analysis of adult and elderly patients showed no clinically relevant relationship of clearance and volume of distribution with body weight.


Obesity:
In one clinical study in morbidly obese patients, sugammadex 2 mg/kg and 4 mg/kg was dosed according to actual body weight (n=76) or ideal body weight (n=74). Sugammadex exposure increased in a dose-dependent, linear manner following administration according to actual body weight or ideal body weight. No clinically relevant differences in pharmacokinetic parameters were observed between morbidly obese patients and the general population.