Cymbalta

Cymbalta Mechanism of Action

duloxetine

Manufacturer:

Eli Lilly

Distributor:

Zuellig
Full Prescribing Info
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Pharmacology: Pharmacodynamics: Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.
Neurochemical and behavioral studies in laboratory animals showed an enhancement of both serotonin and noradrenaline neurotransmission in the CNS. Duloxetine also normalized pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behavior in a model of persistent pain. The presumed mechanism of action of duloxetine in the treatment of both the emotional and somatic symptoms of depression is thought to be due to its inhibition of neuronal uptake of serotonin and noradrenaline, and a resultant increase in serotonergic and noradrenergic neurotransmission in the CNS.
Duloxetine (Cymbalta) was studied in a clinical program involving 2951 patients (1,259 patient-years of exposure) meeting DSM-IV criteria for major depression. The efficacy of Duloxetine (Cymbalta) at the recommended dose of 60 mg once a day was demonstrated in two out of two randomized, double blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder. Overall, Duloxetine (Cymbalta) efficacy has been demonstrated at daily doses between 60 and 120 mg in a total of four out of six randomized, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder.
Duloxetine (Cymbalta) demonstrated statistical superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score (including both the emotional and somatic symptoms of depression). Response and remission rates were also statistically significantly higher with Duloxetine (Cymbalta) compared with placebo. Only a small proportion of patients included in pivotal clinical trials had severe depression (baseline HAM-D >25). In a relapse prevention study, patients responding to 12-weeks of acute treatment with open-label Duloxetine (Cymbalta) 60 mg once daily were randomized to either Duloxetine (Cymbalta) 60 mg once daily or placebo for a further 6-months. Duloxetine (Cymbalta) 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse.
The incidence of relapse during the 6-months double-blind follow-up period was 17% and 29% for duloxetine and placebo, respectively.
The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system.
Pharmacokinetics: Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolized by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, smoking status and CYP2D6 metabolizer status.
Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). These changes do not have any clinical significance.
Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment Duloxetine is extensively metabolized and the metabolites are excreted principally in urine. Both cytochromes P450-CYP2D6 and P450-CYP1A2 catalyze the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy, 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolizers with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of duloxetine are higher in these patients.
The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours). After an intravenous dose the plasma clearance of duloxetine ranges from 22 L/hr to 46 L/hr (mean of 36 L/hr). Apparent plasma clearance of duloxetine ranges from 33 to 261 L/hr (mean of 101 L/hr).
Special populations: Gender: Pharmacokinetic differences have been identified between males and females (apparent plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a lower dose for female patients.
Age: Pharmacokinetic differences have been identified between younger and elderly females (≥65 years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the magnitude of these changes is not sufficient to justify adjustments to the dose. As a general recommendation, caution should be exercised when treating the elderly (see Dosage & Administration and Precautions).
Renal impairment: End stage renal disease patients receiving dialysis had a 2-fold higher duloxetine Cmax and AUC values compared to healthy subjects. Pharmacokinetic data on duloxetine is limited in patients with mild or moderate renal impairment.
Hepatic impairment: Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic insufficiency.
Toxicology: Preclinical safety data: Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats.
Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat carcinogenicity study. The underlying mechanism and the clinical relevance are unknown.
Female mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown.
Reproductive performance was not affected in male rats receiving duloxetine (45 mg/kg/day). Female rats receiving duloxetine (45 mg/kg/day) had a decrease in maternal food consumption and body weight, estrous cycle disruption, decreased live birth indices and progeny survival, and progeny growth retardation at systemic exposure levels estimated to be at the most at maximum clinical exposure (AUC). In an embryo toxicity study in the rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic exposure levels below the maximum clinical exposure (AUC). No malformations were observed in another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity studies in the rat, duloxetine induced adverse behavioral effects in the offspring at exposures below maximum clinical exposure (AUC).
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