Duloxetine (Page 9 of 14)
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).
Duloxetine delayed-release capsules are in a class of drugs known to affect urethral resistance [see Warnings and Precautions (5.15)].
The effect of duloxetine delayed-release capsules 160 mg and 200 mg administered twice daily (2.7 and 3.3 times the maximum recommended dosage, respectively) to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female adult subjects. No QT interval prolongation was detected. Duloxetine delayed-release capsule appears to be associated with concentration-dependent but not clinically meaningful QT shortening.
Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.
After oral duloxetine delayed-release capsules administration, duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
Effect of Food: Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%.
The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.
Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate.
Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Duloxetine steady-state plasma concentration was comparable in pediatric patients 7 to 17 years of age and adult patients. The average steady-state duloxetine concentration was approximately 30% lower in this pediatric population relative to adult patients. The model-predicted duloxetine steady state plasma concentrations in pediatric patients 7 to 17 years of age were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Duloxetine was administered in the diet to mice and rats for 2 years.
In female mice receiving duloxetine at 140 mg/kg/day (3 times the maximum recommended human dose (MRHD) of 120 mg/day given to children on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (1 time the MRHD given to children). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (2 times the MRHD given to children).
In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (1 time the MRHD given to children) and up to 36 mg/kg/day in males (1.4 times the MRHD given to children) did not increase the incidence of tumors.
Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
Impairment of Fertility
Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (3 times the MRHD given to adolescents on a mg/m2 basis) did not alter mating or fertility.
14 CLINICAL STUDIES
14.1 Overview of the Clinical Trials
The efficacy of duloxetine delayed-release capsules has been established in the following populations in adequate and well-controlled trials:
• Major Depressive Disorder (MDD): 4 short-term (Studies MDD-1, MDD-2, MDD-3, and MDD-4) and 1 maintenance trial (Study MDD-5) in adults [see Clinical Studies (14.2)].
• Generalized Anxiety Disorder (GAD):3 short-term trials in adults (Studies GAD-1, GAD-2, and GAD-3), 1 maintenance trial in adults (Study GAD-4), 1 short-term trial in geriatric patients (Study GAD-5), and 1 short-term trial in pediatric patients 7 to 17 years of age (Study GAD-6) [see Clinical Studies (14.3)].
• Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults (Studies DPNP-1 and DPNP-2) [see Clinical Studies (14.4)].
• Fibromyalgia (FM): Two trials in adults (one of 3 months duration and one of 6 months duration) (Studies FM-1 and FM-2) [see Clinical Studies (14.5)].
• Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) (Studies CLBP-1 and CLBP-3) and one 13-week trial in adult patients with chronic pain due to osteoarthritis (OA) (Study OA-1) [see Clinical Studies (14.6)].
Additionally, a summary of the following trials that did not demonstrate efficacy are presented below: Study FM-3 (a 16-week trial in adult patients with fibromyalgia), Study CLBP-2 (a 13-week trial in adult patients with CLBP), and Study OA-2 (a 13-week trial in adult patients with chronic pain due to OA).
Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
14.2 Major Depressive Disorder in Adults
The efficacy of duloxetine delayed-release capsules as a treatment for MDD in adults was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 to 83 years) meeting DSM-IV criteria for MDD:
• In Studies MDD-1 and MDD-2, patients were randomized to duloxetine delayed-release capsules 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks
• In Study MDD-3, patients were randomized to duloxetine delayed-release capsules 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks • In Study MDD-4, patients were randomized to duloxetine delayed-release capsules 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks.
In all four trials, duloxetine delayed-release capsules demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (see Table 8). There is no evidence that doses greater than 60 mg/day confer additional benefits.
In all of these clinical trials, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Table 8: Summary of the Primary Efficacy Results for Adult Trials in MDD
|Study Number||Treatment Group||Primary Efficacy Measure: HAMD-17|
|Mean Baseline Score (SD)||LS Mean Change from Baseline (SE)||Placebo-subtracted Differencea (95% CI)|
|Study MDD-1||Duloxetine delayed-release capsules (60 mg/day)b||21.5 (4.1)||-10.9 (0.7)||-4.9 (-6.8, -2.9)|
|Placebo||21.1 (3.71)||-6.1 (0.69)||—|
|Study MDD-2||Duloxetine delayed-release capsules (60 mg/day)b||20.3 (3.32)||-10.5 (0.71)||-2.2 (-4, -0.3)|
|Placebo||20.5 (3.42)||-8.3 (0.67)||—|
|Study MDD-3||Duloxetine delayed-release capsules (20 mg BID)b||18.6 (5.85)||-7.4 (0.8)||-2.4 (-4.7, -0.2)|
|Duloxetine delayed-release capsules (40 mg BID)b||18.1 (4.52)||-8.6 (0.81)||-3.6 (-5.9, -1.4)|
|Placebo||17.2 (5.11)||-5 (0.81)||—|
|Study MDD-4||Duloxetine delayed-release capsules (40 mg BID)b||19.9 (3.54)||-11 (0.49)||-2.2 (-3.6, -0.9)|
|Duloxetine delayed-release capsules (60 mg BID)b||20.2 (3.41)||-12.1 (0.49)||-3.3 (-4.7, -1.9)|
|Placebo||19.9 (3.58)||-8.8 (0.5)||—|
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included.
a Difference (drug minus placebo) in least-squares mean change from baseline.b Dose statistically significantly superior to placebo.
In Study MDD-5, 533 adult patients meeting DSM-IV criteria for MDD received duloxetine delayed-release capsules 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment [defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD] were randomly assigned to continuation of duloxetine delayed-release capsules at the same dosage (N=136) or to placebo (N=142) for 6 months.
In Study MDD-5, patients on duloxetine delayed-release capsules experienced a statistically significantly longer time to relapse of depression than did patients on placebo (see Figure 1). Relapse was defined as an increase in the CGI–S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit.
Figure 1: Cumulative Proportiona of Adult Patients with MDD Relapse (Study MDD-5)
a Kaplan-Meier estimator method.
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