Chemical formula: C₂₀H₂₄N₂O₂ Molecular mass: 324.417 g/mol PubChem compound: 441074
Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6 (CYP2D6), which catalyses a major biotransformation pathway for dextromethorphan.
Quinidine sulfate is a specific inhibitor of CYP2D6-dependent oxidative metabolism used to increase the systemic bioavailability of dextromethorphan.
Following single and repeated combination doses of dextromethorphan 23 mg / quinidine 9 mg, subjects had an approximately 20-fold increase in dextromethorphan exposure compared to subjects given dextromethorphan without quinidine.
Following repeated doses of dextromethorphan 15 mg / quinidine 9 mg, maximal plasma concentrations (Cmax) of quinidine are reached approximately 2 hours after dosing.
The mean plasma Cmax of quinidine following dextromethorphan 15 mg / quinidine 9 mg twice daily in subjects with PBA was 1 to 3% of the therapeutic concentrations associated with antiarrhythmic efficacy (2 to 5 µg/mL).
Food does not affect the exposure of quinidine significantly.
After administration of the combination product, 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.
After combined administration of dextromethorphan/quinidine, the quinidine component serves to selectively inhibit CYP2D6-dependent oxidative metabolism of dextromethorphan, thus increasing dextromethorphan plasma concentrations. In the presence of quinidine, CYP3A4-dependent oxidative metabolism is believed to play a greater role in dextromethorphan elimination.
After administration of dextromethorphan/quinidine to 14 extensive metabolizers, the elimination halflife of dextromethorphan was 18.8 hours and the elimination half-life of quinidine was 9.6 hours.
Quinidine is metabolized by CYP3A4. There are several hydroxylated metabolites of quinidine. The major metabolite is 3-hydroxyquinidine, which is considered to be at least half as pharmacologically active as quinidine with respect to cardiac effects such as QT prolongation. There are currently limited data on the magnitude of the effect of CYP3A4 inhibitors on the pharmacokinetic parameters of quinidine and its metabolites, including the potential for accumulation at steady state.
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.
Plasma concentrations of dextromethorphan and dextrorphan are proportional to dextromethorphan dose in the presence of a fixed dose of quinidine. Quinidine plasma concentrations are proportional to quinidine dose.
The potential for dextromethorphan and quinidine to inhibit or induce cytochrome P450 in vitro were evaluated in human microsomes. Quinidine did not inhibit (<30% inhibition) CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4 in human microsomes at concentrations up to 5 µM. Quinidine inhibited CYP2D6 with a half maximal inhibitory concentration (IC50) of less than 0.05 µM. Neither dextromethorphan nor quinidine induced CYP1A2, CYP2B6 or CYP3A4 in human hepatocytes at concentrations up to 4.8 µM.
Based on the results of transporter inhibition studies drug-drug interactions related to dextromethorphan inhibition of P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3 or BSEP are not expected during treatment with combined dextromethorphan/quinidine. Dextromethorphan has been shown to be a mild/moderate inhibitor of the OCT1 transporter in vitro. The clinical relevance of this observation to drugs that are OCT1 substrates, such as metformin, is unknown.
Based on literature citations, drug-drug interactions as a result of quinidine inhibition of OATP1B1, OCT1, OCT2, OAT3, BSEP, MATE1, and MATE2-K are not expected.
The pharmacokinetics of dextromethorphan/quinidine have not been investigated systematically in elderly subjects (aged >65 years) although such subjects were included in the clinical programme (14% ≥65 years, 2% ≥75 years).
A population pharmacokinetic analysis of 170 subjects (148 subjects <65 years old and 22 subjects ≥65 years old) administered dextromethorphan 23 mg / quinidine 26 mg revealed similar pharmacokinetics in subjects <65 years and those ≥65 years of age.
A population pharmacokinetic analysis based on data from 109 subjects (75 male; 34 female) showed no apparent gender differences in the pharmacokinetics of dextromethorphan/quinidine.
A population pharmacokinetic analysis of race with 109 subjects (21 Caucasian; 71 Hispanic; 18 Black) revealed no apparent racial differences in the pharmacokinetics of dextromethorphan/quinidine.
In a study of a combination dose of dextromethorphan 23 mg / quinidine 26 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. Dextromethorphan/quinidine has not been studied in patients with severe renal impairment.
In a study of a combination dose of dextromethorphan 23 mg / quinidine 26 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. Quinidine clearance is unaffected, although there is an increased volume of distribution that leads to an increase in the elimination half-life. Patients with moderate hepatic impairment showed an increased frequency of adverse reactions. Therefore, dosage adjustment is not required in patients with mild and moderate hepatic impairment, although additional monitoring for adverse reactions should be considered in patients with moderate hepatic impairment. Dose increase, if warranted, should be undertaken with caution in these patients. Neither dextromethorphan alone nor dextromethorphan/quinidine has been evaluated in patients with severe hepatic impairment.
The quinidine component is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone. Approximately 7-8% of individuals of Caucasian descent, 3-6% of Black African descent, 2-3% of Arab descent and 1-2% of Asian descent generally lack the capacity to metabolize CYP2D6 substrates and are classified as Poor Metabolizer (PMs). The quinidine component is not expected to contribute to the effectiveness of combined dextromethorphan/quinidine in PMs, but adverse reactions of the quinidine component are still possible.
Approximately 1-10% of individuals of Caucasian descent, 5-30% of Black African descent, 12-40% of Arab descent and 1% of Asian descent exhibit increased metabolic activity for CYP2D6 substrates and are classified as Ultra-rapid Metabolizer (UMs). In such UM patients, dextromethorphan is rapidly metabolised, leading to lower, potentially subtherapeutic concentrations.
The pharmacokinetics of dextromethorphan/quinidine in paediatric patients has not been studied.
Non-clinical data reveal no special hazard for a genotoxicity or carcinogenic potential, nor for fertility impairment.
In embryo-fetal and developmental toxicity studies (rats and rabbits) with dextromethorphan hydrobromide/quinidine sulfate, abnormalities were observed at mid and high dose with reduced ossification from the lowest dose in rats which is approximately 1 and 50 times the human dose of 30/18 mg/day on a mg/m² basis, respectively. The no effect dose in rabbits is 2 and 60 times higher than the RHD.
In the pre and post-natal developmental study, slight developmental delay was seen in offspring at the mid- and high-doses. Pup survival and pup weight were slightly decreased from the lowest dose corresponding approximately to 1and 50 times the human dose of 30/18 mg/kg on a mg/m² basis, for dextromethorphan hydrobromide and quinidine sulfate, respectively.
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