Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2    Pharmacodynamics

Cardiac Electrophysiology
The effect of dextromethorphan 30 mg/quinidine 10 mg (for 7 doses) on QTc prolongation was evaluated in a randomized, double-blind (except for moxifloxacin), placebo- and positive-controlled (400 mg moxifloxacin) crossover thorough QT study in 50 fasted normal healthy men and women with CYP2D6 extensive metabolizer (EM) genotype. Mean changes in QTcF were 6.8 ms for dextromethorphan 30 mg/quinidine 10 mg and 9.1 ms for the reference positive control (moxifloxacin). The maximum mean (95% upper confidence bound) difference from placebo after baseline correction was 10.2 (12.6) ms. This test dose is adequate to represent the steady state exposure in patients with CYP2D6 extensive metabolizer phenotype.

The effects of supratherapeutic doses of dextromethorphan/quinidine (30 mg/30mg and 60mg/60mg, for 7 doses) on QTc prolongation was evaluated in a randomized, placebo-controlled, double-blind, crossover design with an additional open-label positive control (400-mg moxifloxacin) arm in 36 healthy volunteers.
The maximum mean (95% upper confidence bound) differences from placebo after baseline-correction were 10.2 (14.6) and 18.4 (22.7) ms following dextromethorphan/quinidine doses of 30 mg/30 mg and 60/60 mg, respectively. The supratherapeutic doses are adequate to represent exposure increases due to drug-drug interactions and organ dysfunctions.

Pharmacokinetic Properties

12.3    Pharmacokinetics
NUEDEXTA contains dextromethorphan and quinidine, both of which are metabolized primarily by liver enzymes. Quinidine’s primary pharmacological action in NUEDEXTA is to competitively inhibit the metabolism of dextromethorphan catalyzed by CYP2D6 in order to increase and prolong plasma concentrations of dextromethorphan [see Warnings and Precautions (5.4), (5.8), and Clinical Pharmacology (12.5)].
Studies were conducted with the individual components of NUEDEXTA in healthy subjects to determine single-dose and multiple-dose kinetics of orally administered dextromethorphan in combination with quinidine.
The increase in dextromethorphan levels appeared approximately dose proportional when the dextromethorphan dose was increased from 20 mg to 30 mg in the presence of 10 mg of quinidine.

Absorption
Following single and repeated combination doses of dextromethorphan 30 mg/quinidine 10 mg, dextromethorphan/quinidine -treated subjects had an approximately 20-fold increase in dextromethorphan exposure compared to dextromethorphan given without quinidine.

Following repeated doses of dextromethorphan 30 mg/quinidine 10 mg and dextromethorphan 20 mg/ quinidine 10 mg (NUEDEXTA), maximal plasma concentrations (Cmax) of dextromethorphan are reached approximately 3 to 4 hours after dosing and maximal plasma concentrations of quinidine are reached approximately 1 to 2 hours after dosing.

In extensive metabolizers, mean Cmax and AUC0-12 values of dextromethorphan and dextrorphan increased as doses of dextromethorphan increased from 20 to 30 mg; mean Cmax and AUC0-12 values of quinidine appeared similar.

The mean plasma Cmax of quinidine following twice daily co-administration of dextromethorphan 30 mg/ quinidine 10 mg in patients with PBA was within 1 to 3% of the concentrations required for antiarrhythmic efficacy (2 to 5 mcg/mL).

NUEDEXTA may be taken without regard to meals as food does not affect the exposure of dextromethorphan and quinidine significantly.

Distribution
After NUEDEXTA administration, protein binding remains essentially the same as that after administration of the individual components; dextromethorphan is approximately 60-70% protein bound and quinidine is approximately 80-89% protein bound.

Metabolism and Excretion
NUEDEXTA is a combination product containing dextromethorphan and quinidine. Dextromethorphan is metabolized by CYP2D6 and quinidine is metabolized by CYP3A4. After dextromethorphan 30 mg/ quinidine 30 mg administration in extensive metabolizers, the elimination half-life of dextromethorphan was approximately 13 hours and the elimination half-life of quinidine was approximately 7 hours.

There are several hydroxylated metabolites of quinidine. The major metabolite of quinidine is 3-hydroxyquinidine. The 3-hydroxymetabolite is considered to be at least half as pharmacologically active as quinidine with respect to cardiac effects such as QT prolongation.

When the urine pH is less than 7, about 20% of administered quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH-dependent) tubular reabsorption.

Specific Populations

Geriatric Use
The pharmacokinetics of dextromethorphan/quinidine have not been investigated systematically in elderly subjects (aged > 65 years), although such subjects were included in the clinical program. A population pharmacokinetic analysis of 170 subjects (148 subjects < 65 years old and 22 subjects ≥ 65 years old) administered dextromethorphan 30 mg/quinidine 30 mg revealed similar pharmacokinetics in subjects < 65 years and those ≥ 65 years of age.
Pediatric Use
The pharmacokinetics of NUEDEXTA in pediatric patients have not been studied.

Gender
A population pharmacokinetic analysis based on data from 109 subjects (75 male; 34 female) showed no apparent gender differences in the pharmacokinetics of NUEDEXTA.

Race
A population pharmacokinetic analysis of race with 109 subjects (20 Caucasian; 71 Hispanic; 18 Black) revealed no apparent racial differences in the pharmacokinetics of NUEDEXTA.

Renal Impairment
In a study of a combination dose of dextromethorphan 30 mg/quinidine 30 mg TWICE DAILY in 12 subjects with mild (CLCR 50-80 mL/min) or moderate (CLCR 30-50 mL/min) renal impairment (6 each) compared to 9 healthy subjects (matched in gender, age, and weight range to impaired subjects), subjects showed little difference in quinidine or dextromethorphan pharmacokinetics compared to healthy subjects. Dose adjustment is, therefore, not required in mild or moderate renal impairment. NUEDEXTA has not been studied in patients with severe renal impairment.

Hepatic Impairment
In a study of a combination dose of dextromethorphan 30 mg/quinidine 30 mg TWICE DAILY in 12 subjects with mild or moderate hepatic impairment (as indicated by the Child-Pugh method; 6 each) compared to 9 healthy subjects (matched in gender, age, and weight range to impaired subjects), subjects with moderate hepatic impairment showed similar dextromethorphan AUC and Cmax and clearance compared to healthy subjects.
Mild to moderate hepatic impairment had little effect on quinidine pharmacokinetics. Patients with moderate impairment showed an increased frequency of adverse events. Therefore, dosage adjustment is not required in patients with mild and moderate hepatic impairment, although additional monitoring for adverse reactions should be considered. Quinidine clearance is unaffected by hepatic cirrhosis, although there is an increased volume of distribution that leads to an increase in the elimination half-life. Neither dextromethorphan alone nor NUEDEXTA has been evaluated in patients with severe hepatic impairment.

12.4    Drug-Drug Interactions
The potential for dextromethorphan and quinidine to inhibit or induce cytochrome P450 in vitro were evaluated in human microsomes. Dextromethorphan did not inhibit (< 20% inhibition) any of the tested isoenzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in human liver microsomes at concentrations up to 5 microM. Quinidine did not inhibit (< 30% inhibition) CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4 in human microsomes at concentrations up to 5 microM. Quinidine inhibited CYP2D6 with a half maximal inhibitory concentration (IC50) of less than 0.05 microM. Neither dextromethorphan nor quinidine induced CYP1A2, CYP2B6 or CYP3A4 in human hepatocytes at concentrations up to 4.8 microM.

Desipramine (CYP2D6 substrate)
Co-administration of dextromethorphan 30 mg/quinidine 30 mg with the tricyclic antidepressant desipramine, a CYP2D6 substrate, when desipramine was given at a dose of 25 mg once daily in 13 healthy volunteers resulted in an approximately 8-fold increase in steady state desipramine exposure (Cmin) compared to desipramine given alone. Therefore, concomitant administration of NUEDEXTA and drugs undergoing CYP2D6 metabolism should be evaluated for appropriate dose adjustment or alternative medication if the concomitant medication depends primarily on CYP2D6 metabolism and has a narrow therapeutic index, or if it relies on CYP2D6 for conversion to an active species [see Warnings and Precautions (5.4)].


Paroxetine (CYP2D6 inhibitor and substrate)
Co-administration of the selective serotonin reuptake inhibitor paroxetine and a higher combination dose of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) was studied in 27 healthy volunteers. Group 1 (N = 14) received paroxetine 20 mg once daily for 12 days followed by the addition of dextromethorphan 30 mg/quinidine 30 mg twice daily for 8 days. Group 2 (N = 13) received dextromethorphan 30 mg/quinidine 30 mg twice daily for 8 days followed by the addition of paroxetine 20 mg once daily for 12 days. Dextromethorphan exposure (AUC0-12) and Cmax increased by 1.5 fold and
1.4 fold, respectively, and quinidine exposure (AUC0-12) and Cmax increased by 1.4 fold and 1.3 fold, respectively, and dextrorphan exposure (AUC0-12) and Cmax decreased by 14% and 18%, respectively, and paroxetine exposure (AUC0-24) and Cmax increased by 2.3 fold and 2.0 fold, respectively, when paroxetine was added to the combination dose of dextromethorphan/quinidine at steady state (Group 2).

When the combination dose of dextromethorphan/quinidine was added to paroxetine at steady state (Group 1), paroxetine exposure (AUC0-24) and Cmax increased by 1.7 fold and 1.5 fold, respectively, while dextromethorphan and quinidine exposure did not change significantly and dextrorphan exposure (AUC0-12) and Cmax decreased by 34% and 33%, respectively.

Based on these results, when NUEDEXTA is prescribed with drugs such as paroxetine that inhibit or are extensively metabolized by CYP2D6, consideration should be given to initiating treatment with a lower dose.
The dose of paroxetine can then be adjusted based on clinical response; however, dosage above 35 mg/day is not recommended [see Warnings and Precautions (5.4)].

NMDA receptor antagonists (memantine)
A drug interaction study was conducted between a higher combination dose of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) and memantine 20 mg/day to investigate the pharmacokinetic and pharmacodynamic interactions in 52 healthy subjects. Both dextromethorphan and memantine are antagonists of the N-methyl-D-aspartate (NMDA) receptor, which could theoretically result in an additive effect at NMDA receptors and potentially an increased incidence of adverse events. There was no significant difference in the plasma concentrations of dextromethorphan and dextrorphan before and after the administration of memantine. Plasma concentrations of quinidine increased 20-30% when memantine was added to dextromethorphan 30 mg/quinidine 30 mg.

12.5    Pharmacogenomics
The quinidine component of NUEDEXTA is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone. Approximately 7-10% of Caucasians and 3-8% of African Americans generally lack the capacity to metabolize CYP2D6 substrates and are classified as PMs. The quinidine component of NUEDEXTA is not expected to contribute to the effectiveness of NUEDEXTA in PMs, but adverse events of the quinidine are still possible. In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat with NUEDEXTA [see Warnings and Precautions (5.4),(5.8), and Clinical Pharmacology (12.3)].