Mechanism Of Action
Amisulpride is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist. D2 receptors are located in the chemoreceptor trigger zone (CTZ) and respond to the dopamine released from the nerve endings. Activation of CTZ relays stimuli to the vomiting center which is involved in emesis. Studies in multiple species indicate that D3 receptors in the area postrema also play a role in emesis. Studies conducted in ferrets have shown that amisulpride inhibits emesis caused by apomorphine, with an estimated ED50 of less than 1 mcg/kg, subcutaneously; and inhibits cisplatin-induced emesis at 2 mg/kg and morphine-induced emesis at 3 to 6 mg/kg, when given intravenously.
Amisulpride has no appreciable affinity for any other receptor types apart from low affinities for 5-HT2B and 5-HT7 receptors.
In 40 healthy Caucasian and Japanese subjects, the maximum mean difference (95% upper confidence bound) in QTcF from placebo after baseline-correction (ΔΔQTcF) was 5.0 (7.1) milliseconds after a 2-minute intravenous infusion of 5 mg BARHEMSYS and 23.4 (25.5) milliseconds after an 8-minute intravenous infusion of 40 mg BARHEMSYS [see WARNINGS AND PRECAUTIONS].
A significant exposure-response relationship was identified between amisulpride concentration and ΔΔQTcF. Using this exposure-response relationship, 10 mg BARHEMSYS infused intravenously over 1 min has a maximal predicted (95% upper prediction interval) ΔΔQTcF of 13.4 (15.1) milliseconds.
The recommended infusion rate is 1 to 2 minutes for 5 mg or 10 mg of BARHEMSYS [see DOSAGE AND ADMINISTRATION].
After an intravenous infusion, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases to about 50% of the peak value within approximately 15 minutes. The AUC(0-∞) increases dose-proportionally in the dose range from 5 mg to 40 mg (4-times the maximum recommended dose).
The following mean pharmacokinetic parameters of amisulpride were observed following a single 5 or 10 mg intravenous dose in adult healthy subjects and surgical patients.
Table 2. Summary of Key Pharmacokinetic Parameters of Amisulpride fromClinical Studies
|SingleDose||Infusion Duration (minutes)||Number of Subjects||Mean (SD)|
|Peak Plasma Concentration (ng/mL)||AUC(0-∞) (ng·h/mL)|
|Healthy Subjects||5 mg||2||39||200 (139)||154 (30)|
|Healthy Subjects||10 mg||1||29||451 (230)||136 (28)a|
|Patients||5 mg||1 to 2||26b||161 (58)||260 (65)|
|27c||127 (64)||204 (94)|
|Patients||10 mg||1 to 2||31c||285 (446)||401 (149)|
|a AUC(0-2 hr)|
b Patients in a clinical trial for prophylaxis of PONV
c Patients in clinical trials for treatment of PONV
Following intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 L in surgical patients and 171 L in healthy subjects.
Amisulpride distributes into erythrocytes. Plasma protein binding is 25% to 30% in the concentration range from 37 to 1850 ng/mL.
The mean elimination half-life is approximately 4 to 5 hours and similar between healthy subjects and surgical patients. Population pharmacokinetic analysis estimated that the plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects.
In a mass balance study, no metabolites were detectable in plasma while four metabolites were identified in urine and feces. Each metabolite accounts for less than 7% of the dose. In vitro amisulpride is not metabolized by major cytochrome P450 enzymes.
After intravenous administration of amisulpride, 74% and 23% of the administered dose was recovered in urine and feces, respectively. 58% and 20% of the dose was excreted as unchanged amisulpride in urine and feces, respectively.
Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects suggesting that amisulpride undergoes active renal secretion.
Age, Sex, And Racial Groups
No clinically significant effect on the pharmacokinetics of amisulpride was observed based on age (18 to 90 years), sex, or race.
Patients With Renal Impairment
In surgical patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), the Cmax of amisulpride was not significantly different and the AUC(0-∞) of amisulpride increased about 1.3-fold compared to patients with normal renal function. The pharmacokinetics of amisulpride in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been adequately studied in clinical trials [see Use In Specific Populations].
Drug Interaction Studies
No clinical drug interaction trials have been conducted with BARHEMSYS.
In Vitro Studies
Cytochrome P450-Related Metabolism
In vitro, amisulpride did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, or induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4.
In vitro, amisulpride was not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.
Amisulpride inhibits MATE1 and MATE2-K transporters.
Amisulpride does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 at therapeutic concentrations.
Amisulpride is a substrate for P-gp, BCRP, OCT1, MATE1 and MATE2-K, but not a substrate for OATP1B1, OATP1B3, OAT1, OAT3 and OCT2.
Prevention Of Postoperative Nausea And Vomiting
The efficacy of BARHEMSYS for the prevention of PONV was evaluated in two randomized, double-blind, placebo-controlled, multi-center trials in patients undergoing general anesthesia and elective surgery (Study 1 and Study 2). In Study 1 (NCT01991860), patients received monotherapy with BARHEMSYS; while in Study 2 (NCT02337062), patients received BARHEMSYS in combination with one other intravenously administered, non-dopaminergic antiemetic (ondansetron, dexamethasone or betamethasone). In both trials, patients were administered BARHEMSYS at the induction of anesthesia.
Study 1 was conducted in the United States in 342 patients. The mean age was 54 years (range 21 to 88 years); 65% female; 87% White/Caucasian, 12% Black, and 1% Asian race. The treatment groups were similarly matched in terms of risk for PONV with 30% of patients having two risk factors, 47% of patients having three risk factors and 23% of patients having four risk factors.
Study 2 was conducted in the United States and Europe in 1,147 patients. The mean age was 49 years (range 18 to 91 years); 97% female; 75% White/Caucasian, 9% Black, 1% Asian, and 14% of unreported race. The treatment groups were similarly matched in terms of risk for PONV with 56% of patients having three risk factors and 43% of patients having four risk factors.
The primary efficacy endpoint in both trials was Complete Response, defined as absence of any episode of emesis or use of rescue medication within the first 24 hours postoperatively. Results for both trials are shown in Table 3.
Table 3. Complete Response Rates in Adult Patients for the Prevention of PONV Within 24 Hours After End of Surgery in Studies 1 and 2
|Study 1||Study 2|
|BARHEMSYS 5 mgwith Another Antiemetic|
|Placebo with Another Antiemetic|
|Complete Response||78 (44%)||54 (33%)||330 (58%)||268 (47%)|
|Difference (95% CI)*||12%|
|*Unadjusted, nominal 95% confidence interval|
Treatment Of Postoperative Nausea And Vomiting
The efficacy of BARHEMSYS 10 mg as a single dose was evaluated in two randomized, double-blind, placebo-controlled, multi-center trials in patients experiencing PONV after general anesthesia and elective surgery (Study 3 and Study 4). Study 3 (NCT02449291) enrolled patients who had not received prior PONV prophylaxis, whereas Study 4 (NCT02646566) included patients who had received and failed PONV prophylaxis with an antiemetic of another class. Patients were excluded if they had received a D2 receptor antagonist antiemetic.
Study 3 was conducted in 369 patients (mean age 47 years, range 19 to 82 years; 76% female; 82% White/Caucasian, 8% Black, 2% Asian, and 8% of unreported race). Most of the patients had either two risk factors (36%) or three risk factors (53%) for PONV and these percentages were similar between treatment groups.
Study 4 was conducted in 465 patients (mean age 46 years, range 18 to 85 years; 90% female; 82% White/Caucasian, 9% Black, 3% Asian, and 6% of unreported race). Patients had received prior PONV prophylaxis with one or more nondopaminergic antiemetics: a 5-HT3-antagonist in 77%, dexamethasone in 65% and another antiemetic class in 10%. Most of the patients had either three risk factors (43%) or four risk factors (51%) for PONV and these percentages were similar between treatment groups.
For both trials, the primary efficacy endpoint was Complete Response defined as absence of any episode of emesis or use of rescue medication within the first 24 hours after treatment (excluding emesis within the first 30 minutes).
BARHEMSYS Complete Response in both studies is shown in Table 4.
Table 4. Complete Response Rates in Adult Patients for the Treatment of PONV With in 24 Hours After Treatmenta in Studies 3 and 4
|BARHEMSYS 10 mg|
|BARHEMSYS 10 mg|
|Complete Response||59 (31%)||39 (22%)||96 (42%)||67 (29%)|
|Difference (95% CI)c||10% (1%, 19%)||13% (5%, 22%)|
|a Excluding emesis within the first 30 minutes|
b Received prior PONV prophylaxis with one or more non-dopaminergic antiemetics: a 5-HT3-antagonist in 77%, dexamethasone in 65% and another antiemetic class in 10%
c Unadjusted, nominal 95% confidence interval