Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac therapy, other antiarrhythmics class I and III, ATC code: C01BG11.

Mechanism of Action
Vernakalant is an antiarrhythmic medicinal product that acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow impulse conduction. These anti-fibrillatory actions on refractoriness and conduction are thought to suppress re-entry, and are potentiated in the atria during atrial fibrillation. The relative selectivity of vernakalant on atrial versus ventricular refractoriness is postulated to result from the block of currents regulated by ion channels that are expressed in the atria, but not in the ventricles, as well as the unique electrophysiologic condition of the fibrillating atria. However, blockade of cationic currents, including hERG channels and cardiac voltage-dependent sodium channels, which are present in the ventricles has been documented.


Pharmacodynamic effects
In preclinical studies, vernakalant blocks currents in all phases of the atrial action potential, including potassium currents that are expressed specifically in the atria (e.g., the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents). During atrial fibrillation, the frequency- and voltage-dependent block of sodium channels further focuses the action of the medicinal product toward rapidly activating and partially depolarised atrial tissue rather than toward the normally polarised ventricle beating at lower heart rates. Additionally, the ability of vernakalant to block the late component of the sodium current limits effects on ventricular repolarisation induced by blockade of potassium currents in the ventricle. Targeted effects on atrial tissue coupled with block of late sodium current suggests that vernakalant has a low proarrhythmic potential. Overall, the combination of effects of vernakalant on cardiac potassium and sodium currents results in substantial antiarrhythmic effects that are mainly concentrated in the atria.

In an electrophysiological study in patients, vernakalant significantly prolonged atrial effective refractory period in a dose-dependent manner, which was not associated with a significant increase in ventricular effective refractory period. Across the Phase 3 population, vernakalant treated patients had an increase in heart rate-corrected QT (using Fridericia's correction, QTcF) compared to placebo (22.1 ms and 18.8 ms placebo-subtracted peaks after first and second infusions, respectively). By 90 minutes after the start of infusion, this difference was reduced to 8.1 ms.

Clinical efficacy and safety
Clinical Trial Design: The clinical effect of vernakalant in the treatment of patients with atrial fibrillation has been evaluated in three, randomised, double-blind, placebo-controlled studies, (ACT I, ACT II and ACT III) and in an active comparator trial versus intravenous amiodarone (AVRO). Some patients with typical atrial flutter were included in ACT II and ACT III and BRINAVESS was not found to be effective in converting atrial flutter. In clinical studies, the need for anticoagulation prior to administration of vernakalant was assessed as per clinical practice of the treating physician. For atrial fibrillation lasting less than 48 hours, immediate cardioversion was allowed. For atrial fibrillation lasting longer than 48 hours, anticoagulation was required as per treatment guidelines.
ACT I and ACT III studied the effect of vernakalant in the treatment of patients with sustained atrial fibrillation > 3 hours but not more than 45 days in duration. ACT II examined the effect of BRINAVESS on patients who developed atrial fibrillation of < 3 days duration after recently undergoing coronary artery bypass graft, (CABG) and/or valvular surgery (atrial fibrillation occurred more than 1 day but less than 7 days after surgery). AVRO studied the effect of vernakalant versus intravenous amiodarone in patients with recent onset atrial fibrillation (3 hrs to 48 hrs). In all studies, patients received a 10-minute infusion of 3.0 mg/kg vernakalant (or matching placebo) followed by a 15-minute observation period. If the patient was in atrial fibrillation or atrial flutter at the end of the 15-minute observation period, a second 10-minute infusion of 2.0 mg/kg vernakalant (or matching placebo) was administered. Treatment success (responder) was defined as conversion of atrial fibrillation to sinus rhythm within 90 minutes.
Patients who did not respond to treatment were managed by the physician using standard care.

Efficacy in patients with sustained atrial fibrillation, (ACT I and ACT III) Primary efficacy endpoint was the proportion of subjects with short duration atrial fibrillation (3 hours to 7 days) who had a treatment-induced conversion of atrial fibrillation to sinus rhythm for a minimum duration of one minute within 90 minutes of first exposure to study drug. Efficacy was studied in a total of 390 haemodynamically stable adult patients with short duration atrial fibrillation including patients with hypertension (40.5%), ischaemic heart disease (12.8%), valvular heart disease (9.2%) and CHF (10.8%). In these studies treatment with BRINAVESS effectively converted atrial fibrillation to sinus rhythm as compared with placebo (see Table 2).
Conversion of atrial fibrillation to sinus rhythm occurred rapidly (in responders the median time to conversion was 10 minutes from start of first infusion) and sinus rhythm was maintained through 24 hours (97%). The vernakalant dose recommendation is a titrated therapy with two possible dose steps. In the performed clinical studies, the additive effect of the second dose, if any, cannot be independently established.

Table 2: Conversion of Atrial Fibrillation to Sinus Rhythm in ACT I and ACT III Duration of ACT I                                   ACT III
Atrial        BRINAVESS Placebo P-                  BRINAVESS Placebo P-Value† Fibrillation                              Value†
> 3 hours to 74/145           3/75                  44/86        3/84 < 0.0001                         < 0.0001
 7 days      (51.0%)         (4.0%)                (51.2%)      (3.6%) †Cochran-Mantel-Haenszel test

BRINAVESS was shown to provide relief of atrial fibrillation symptoms consistent with conversion to sinus rhythm.

No significant differences in safety or effectiveness were observed based on age, gender, use of rate control medicinal product, use of antiarrhythmic medicinal product, use of warfarin, history of ischaemic heart disease, renal impairment or expression of the cytochrome P450 2D6 enzyme.

Treatment with vernakalant did not affect the response rate to electrical cardioversion (including the median number of shocks or joules required for successful cardioversion) in cases when attempted within 2 to 24 hours of study medicinal product administration.

Conversion of atrial fibrillation in patients with longer-duration atrial fibrillation (> 7 days and ≤ 45 days) assessed as a secondary efficacy endpoint in a total of 185 patients did not show statistically significant differences between vernakalant and placebo.

Efficacy in patients who developed atrial fibrillation post cardiac surgery (ACT II) Efficacy was studied in patients with atrial fibrillation after cardiac surgery in ACT II, a phase 3, double-blind, placebo-controlled, parallel group study (ACT II) in 150 patients with sustained atrial fibrillation (3 hours to 72 hours duration) that occurred between 24 hours and 7 days post coronary artery bypass graft and/or valvular surgery. Treatment with BRINAVESS effectively converted atrial fibrillation to sinus rhythm (47.0% vernakalant, 14.0% placebo; P value = 0.0001). Conversion of atrial fibrillation to sinus rhythm occurred rapidly (median time to conversion 12 minutes from the start of infusion).

Efficacy versus amiodarone (AVRO):
Vernakalant was studied in 116 pts with atrial fibrillation (3 hrs to 48 hrs) including patients with hypertension (74.1%), IHD (19%), valvular heart disease (3.4%) and CHF (17.2%). No patients with NYHA III/IV were included in the study. In AVRO, the amiodarone infusion was given over 2 hours (i.e., 1 hour loading dose of 5 mg/kg, followed by 1 hour maintenance infusion of
50 mg). The primary endpoint was the proportion of patients that achieved sinus rhythm (SR) at 90 minutes after initiating therapy, limiting the conclusions to the effects seen in this time window. Treatment with vernakalant, converted 51.7% of patients to SR at 90 minutes versus 5.2% with amiodarone resulting in a significantly faster conversion rate from AF to SR within the first 90 minutes compared to amiodarone (log-rank P-value < 0.0001).

Efficacy from Post-Marketing Observational Study
In the post-approval safety study SPECTRUM that included 1,778 patients with 2,009 BRINAVESS treatment episodes, effectiveness was assessed as the proportion of patients who converted to sinus rhythm for at least one (1) minute within 90 minutes from the start of the infusion, excluding patients who received electrical cardioversion or intravenous Class I/III antiarrhythmics for cardioversion within the 90-minute window. Overall, vernakalant was effective in 70.2% (1,359/1,936) of these patients. Median time to conversion to SR as reported among all patients who, as per the investigator judgement, converted to SR was 12 minutes and in most of the treatment episodes (60.4%) only one infusion was administered.
The higher cardioversion rate in SPECTRUM as compared to clinical phase 3 studies (70.2% vs 47% to 51%) is correlated with a shorter duration of the duration of the index atrial fibrillation period (median duration of 11.1 hours in SPECTRUM vs 17.7 to 28.2 hours in clinical studies).

If patients who received electrical cardioversion, intravenous antiarrhythmics or oral propafenone/flecainide within 90 minutes from the start of the infusion are regarded as treatment failures in addition to patients who did not convert for one minute within 90 minutes, the conversion rate among the 2,009 patients who received vernakalant was 67.3 % (1,352/2,009). There was no meaningful difference when stratifying the analysis by therapeutic indication (i.e. non-surgery and post-cardiac surgery patients).


Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with vernakalant in all subsets of the paediatric population in atrial fibrillation (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single 10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion of 2 mg/kg with a 15 minute interval between doses.

Distribution
Vernakalant is extensively and rapidly distributed in the body, with a volume of distribution of approximately 2 l/kg. The Cmax and AUC were dose proportional between 0.5 mg/kg and 5 mg/kg. In patients, the typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg. The free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml.


Elimination
Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation and renal excretion are the main mechanisms of elimination in CYP2D6 poor metabolisers. The mean elimination half-life of vernakalant in patients was approximately 3 hours in CYP2D6 extensive metabolisers and approximately 5.5 hours in poor metabolisers. By 24 hours there appears to be insignificant levels of vernakalant.


Special patient groups
Acute vernakalant pharmacokineticsis not significantly influenced by gender, history of congestive heart failure, renal impairment, or concomitant administration of beta blockers and other medicinal products, including warfarin, metoprolol, furosemide and digoxin. In patients with hepatic impairment, exposures were elevated by 9 to 25%. No dose adjustment is required for these conditions, nor on the basis of age, serum creatinine or CYP2D6 metaboliser status.