CLINICAL PHARMACOLOGY
Pharmacodynamics
Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, the antidepressant and pain inhibitory 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 undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Pharmacokinetics
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, CYP2D6 and CYP1A2.
Absorption and Distribution
Orally administered 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. 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%. 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.
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.
Metabolism and Elimination
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 CYP2D6 and CYP1A2 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.
Special Populations
Gender
Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.
Age
The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary (see DOSAGE AND ADMINISTRATION).
Smoking Status
Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.
Race
No specific pharmacokinetic study was conducted to investigate the effects of race.
Renal Insufficiency
Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60-mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. For this reason, Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or severe renal impairment (estimated creatinine clearance [CrCl]<30 mL/min) (see DOSAGE AND ADMINISTRATION). Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance.
Hepatic Insufficiency
Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20-mg dose of Cymbalta, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer (see PRECAUTIONS). It is recommended that duloxetine not be administered to patients with any hepatic insufficiency (see DOSAGE AND ADMINISTRATION).
Nursing Mothers
The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine 40 mg BID was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg BID dosing. Lactation did not influence duloxetine pharmacokinetics. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics (see DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions (also see PRECAUTIONS, Drug Interactions)
Potential for Other Drugs to Affect Duloxetine
Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.
Inhibitors of CYP1A2 — When duloxetine was co-administered with fluvoxamine, a potent CYP1A2 inhibitor, to male subjects (n=14) the AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.
Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations of duloxetine (see PRECAUTIONS, Drug Interactions).
Studies with Benzodiazepines
Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.
Temazepam — Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.
Potential for Duloxetine to Affect Other Drugs
Drugs Metabolized by CYP1A2 — In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Although duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg BID). Duloxetine is thus unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates.
Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of CYP2D6 and increases the AUC and Cmax of drugs metabolized by CYP2D6 (see PRECAUTIONS). Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and that have a narrow therapeutic index should be approached with caution (see PRECAUTIONS, Drug Interactions).
Drugs Metabolized by CYP2C9 — Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, although clinical studies have not been performed.
Drugs Metabolized by CYP3A — Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.
Drugs Metabolized by CYP2C19 — Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.
Studies with Benzodiazepines
Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of lorazepam were not affected by co-administration.
Temazepam — Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of temazepam were not affected by co-administration.
Drugs Highly Bound to Plasma Protein — Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events.
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