Evelyn D. Lobo

Duloxetine: clinical pharmacokinetics and drug interactions.

Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric pH produced by histamine H(2)-receptor antagonists or antacids did not impact the absorption of duloxetine. While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes.

In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine.

AbstractObjective: To determine whether duloxetine is a substrate, inhibitor or inducer of cytochrome P450 (CYP) 1A2 enzyme, using in vitro and in vivo studies in humans. Methods: Human liver microsomes or cells with expressed CYP enzymes and specific CYP inhibitors were used to identify which CYP enzymes catalyse the initial oxidation steps in the metabolism of duloxetine. The potential of duloxetine to inhibit CYP1A2 activity was determined using incubations with human liver microsomes and phenacetin, the CYP1A2 substrate. The potential for duloxetine to induce CYP1A2 activity was determined using human primary hepatocytes treated with duloxetine for 72 hours. Studies in humans were conducted using fluvoxamine, a potent CYP1A2 inhibitor, and theophylline, a CYP1A2 substrate, as probes. The subjects were healthy men and women aged 18–65 years. Single-dose duloxetine was administered either intravenously as a 10-mg infusion over 30 minutes or orally as a 60-mg dose in the presence or absence of steady-state fluvoxamine (100 mg orally once daily). Single-dose theophylline was given as 30-minute intravenous infusions of aminophylline 250 mg in the presence or absence of steady-state duloxetine (60 mg orally twice daily). Plasma concentrations of duloxetine, its metabolites and theophylline were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods and evaluated using mixed-effects ANOVA. Safety measurements included vital signs, clinical laboratory tests, a physical examination, ECG readings and adverse event reports. Results: The in vitro results indicated that duloxetine is metabolized by CYP1A2; however, duloxetine was predicted not to be an inhibitor or inducer of CYP1A2 in humans. Following oral administration in the presence of fluvoxamine, the duloxetine area under the plasma concentration-time curve from time zero to infinity (AUC∞) and the maximum plasma drug concentration (Cmax) significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In the presence of fluvoxamine, the oral bioavailability of duloxetine increased from 42.8% to 81.9%. In the presence of duloxetine, the theophylline AUC∞ and Cmax increased by only 13% (90% CI 7, 18) and 7% (90% CI 2,14), respectively. Coadministration of duloxetine with fluvoxamine or theophylline did not result in any clinically important safety concerns, and these combinations were generally well tolerated. Conclusion: Duloxetine is metabolized primarily by CYP1A2; therefore, coadministration of duloxetine with potent CYP1A2 inhibitors should be avoided. Duloxetine does not seem to be a clinically significant inhibitor or inducer of CYP1A2; therefore, dose adjustment of CYP1A2 substrates may not be necessary when they are coadministered with duloxetine.

Pharmacokinetics of Duloxetine in Breast Milk and Plasma of Healthy Postpartum Women

AbstractObjective: The purpose of this study was to characterize duloxetine pharmacokinetics in the breast milk and plasma of lactating women and to estimate the duloxetine dose that an infant might consume if breastfed. Methods: This open-label study included six healthy women aged 22–35 years who stopped nursing during and after the study. Duloxetine 40 mg was given orally every 12 hours for 3.5 days; seven plasma and milk samples over 12 hours were obtained after the seventh dose. Plasma and milk samples were analysed using validated liquid chromatography-tandem mass spectrometry methods. Safety measures included vital signs, ECGs, laboratory tests, adverse event monitoring and depression rating scales. Results: The mean steady-state milk-to-plasma duloxetine exposure ratio was 0.25 (90% CI 0.18, 0.35). The amount of duloxetine in the breast milk was 7 μg/day (range 4–15 μg/day). The estimated infant dose was 2 μg/kg/day (range 0.6–3 μg/kg/day), which is 0.14% of the maternal dose. Dizziness, nausea and fatigue were commonly reported adverse events. No clinically important changes in safety measures occurred. Conclusion: Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth of those in maternal plasma. As the safety of duloxetine in infants is unknown, prescribers should carefully assess, on an individual basis, the potential risks of duloxetine exposure to infants and the benefits of nursing an infant when the mother is on duloxetine therapy.

Population pharmacokinetics of orally administered duloxetine in patients: implications for dosing recommendation.

OBJECTIVES: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment. METHODS: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 131). Patients were given 20-60 mg/day of oral duloxetine once or twice daily (the highest dose studied was 120 mg/day). A population pharmacokinetic model was developed using a nonlinear mixed-effects modelling method. Covariates including bodyweight, age, sex, ethnicity, smoking status, disease condition, dose, dosing regimen and creatinine clearance were tested for their influence on duloxetine pharmacokinetics. The final model was used to predict steady-state duloxetine concentration-time profiles in various patient subgroups. RESULTS: Duloxetine pharmacokinetics in patients were described by a one-compartmental pharmacokinetic model. The interpatient variability in apparent oral clearance (CL/F) was 59% and the interpatient variability in the apparent volume of distribution after oral administration (V(d)/F) was 97%. The residual error was 31%. Sex, smoking status, age and dose had a statistically significant effect on CL/F, whereas the V(d)/F was influenced by ethnicity. CL/F was 40% lower in females than in males and 30% lower in nonsmokers than in smokers. CL/F decreased with increasing dose and age. The V(d)/F in Hispanic patients was twice that of non-Hispanic patients. Simulations showed a considerable overlap in duloxetine exposure between the identified patient subgroups. CONCLUSION: Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.

Population Pharmacokinetics of Orally Administered Duloxetine in Patients

AbstractObjectives: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment. Methods: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 131). Patients were given 20–60 mg/day of oral duloxetine once or twice daily (the highest dose studied was 120 mg/day). A population pharmacokinetic model was developed using a nonlinear mixed-effects modelling method. Covariates including bodyweight, age, sex, ethnicity, smoking status, disease condition, dose, dosing regimen and creatinine clearance were tested for their influence on duloxetine pharmacokinetics. The final model was used to predict steady-state duloxetine concentration-time profiles in various patient subgroups. Results: Duloxetine pharmacokinetics in patients were described by a one-compartmental pharmacokinetic model. The interpatient variability in apparent oral clearance (CL/F) was 59% and the interpatient variability in the apparent volume of distribution after oral administration (Vd/F) was 97%. The residual error was 31%. Sex, smoking status, age and dose had a statistically significant effect on CL/F, whereas the Vd/F was influenced by ethnicity. CL/F was 40% lower in females than in males and 30% lower in nonsmokers than in smokers. CL/F decreased with increasing dose and age. The Vd/F in Hispanic patients was twice that of non-Hispanic patients. Simulations showed a considerable overlap in duloxetine exposure between the identified patient subgroups. Conclusion: Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.

Effects of Varying Degrees of Renal Impairment on the Pharmacokinetics of Duloxetine

BackgroundDuloxetine is indicated for patients with a variety of conditions, and some of these patients may have mild to moderate degrees of renal impairment. Renal impairment may affect the pharmacokinetics of a drug by causing changes in absorption, distribution, protein binding, renal excretion or nonrenal clearance. As duloxetine is highly bound to plasma proteins and its metabolites are renally excreted, it is prudent to evaluate the effect of renal insufficiency on exposure to duloxetine and its metabolites in the systemic circulation.ObjectiveThe aim of this study was to evaluate the effects of varying degrees of renal impairment on duloxetine pharmacokinetics in a single-dose phase I study and using pooled steady-state pharmacokinetic data from phase II/III trials.MethodsIn the phase I study, a single oral dose of duloxetine 60 mg was given to 12 subjects with end-stage renal disease (ESRD) and 12 matched healthy control subjects. In the phase II/III trials (n = 463 patients), duloxetine 20–60 mg was given as once- or twice-daily doses. Duloxetine and metabolite concentrations in plasma were determined using liquid chromatography with tandem mass spectrometry. Noncompartmental methods (phase I: duloxetine and its metabolites) and population modelling methods (phase II/III: duloxetine) were used to analyse the pharmacokinetic data.ResultsThe maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of duloxetine were ∼2-fold higher in subjects with ESRD than in healthy subjects, which appeared to reflect an increase in oral bioavailability. The Cmax and AUC of two major inactive conjugated metabolites were as much as 2- and 9-fold higher, respectively, reflecting reduced renal clearance of these metabolites. Population pharmacokinetic results indicated that mild or moderate renal impairment, assessed by creatinine clearance (CLCR) calculated according to the Cockcroft-Gault formula, did not have a statistically significant effect on pharmacokinetic parameters of duloxetine. Values for the apparent total body clearance of duloxetine from plasma after oral administration (CL/F) in subjects with ESRD were similar to CL/F values in patients with normal renal function or with mild or moderate renal impairment.ConclusionDose adjustments for duloxetine are not necessary for patients with mild or moderate renal impairment (CLcr ≥30 mL/min). For patients with ESRD or severe renal impairment (CLcr <30 mL/min), exposures of duloxetine and its metabolites are expected to increase; therefore, duloxetine is not generally recommended for these patients.

Effects of Duloxetine on the Pharmacodynamics and Pharmacokinetics of Warfarin at Steady State in Healthy Subjects

This study evaluated the pharmacodynamics and pharmacokinetics of once‐daily dosing of warfarin at steady state when taken concomitantly with once‐daily doses of duloxetine. Healthy subjects with a stable international normalized ratio (INR) of 1.5 to 2.0 on an individualized fixed dose of warfarin (2–9 mg) in period 1 received daily warfarin and duloxetine (60 mg for 14 days [n = 15] or 60 mg for 4 days, then 120 mg for 10 days [n = 15]) in period 2. Across the 14‐day period when warfarin was coadministered with duloxetine, the least squares mean INR changes from baseline (warfarin alone) ranged from −0.05 to +0.07, and the 90% confidence intervals ranged from −0.12 to +0.14. Following coadministration of warfarin with 60 mg duloxetine, but not with 120 mg duloxetine, there was a statistically significant prolongation in bleeding time compared to warfarin alone. For both R‐ and S‐warfarin, the 90% confidence interval for the geometric mean ratios of area under the curve (AUCτ,ss) and maximum plasma concentrations (Cmax, ss) between warfarin administered alone and with 60 or 120 mg duloxetine were contained within the bioequivalence limits of 0.8 to 1.25. In conclusion, duloxetine had no clinically or statistically significant effect on the pharmacodynamics or pharmacokinetics of warfarin at steady state.

An open-label safety and pharmacokinetics study of duloxetine in pediatric patients with major depression

OBJECTIVE This preliminary, 32-week study assessed the safety, tolerability, and pharmacokinetics of duloxetine in pediatric patients (aged 7-17 years) with major depressive disorder. METHODS Patients received flexible duloxetine doses of 20-120 mg once daily, with dose changes made based on clinical improvement and tolerability. Pharmacokinetic samples were collected across all duloxetine doses, and data were analyzed using population modeling. Primary outcome measures included treatment-emergent adverse events (TEAEs), vital signs, and Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS Of the 72 enrolled patients, 48 (66.7%) completed acute treatment (18 weeks) and 42 (58.3%) completed extended treatment. Most patients (55/72; 76%) required doses ≥ 60 mg once daily to optimize efficacy based on investigator judgment and Clinical Global Impressions-Severity score. Body weight and age did not significantly affect duloxetine pharmacokinetic parameters. Typical duloxetine clearance in pediatric patients was ≈ 42%-60% higher than that in adults. Four patients (5.6%) discontinued due to TEAEs. Many (36/72, 50%) patients experienced potentially clinically significant (PCS) elevations in blood pressure, with most cases (21/36, 58%) being transient. As assessed via C-SSRS, one nonfatal suicidal attempt occurred, two patients (2.8%) experienced worsening of suicidal ideation, and among the 19 patients reporting suicidal ideation at baseline, 17 (90%) reported improvement in suicidal ideation. CONCLUSION Results suggested that pediatric patients generally tolerated duloxetine doses of 30 to 120 mg once daily, although transient PCS elevations in blood pressure were observed in many patients. Pharmacokinetic results suggested that adjustment of total daily dose based on body weight or age is not warranted for pediatric patients and different total daily doses may not be warranted for pediatric patients relative to adults.

Pharmacokinetics and Tolerability of Duloxetine following Oral Administration to Healthy Chinese Subjects

ObjectivesThe objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60mg dosing.MethodsThis was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations.ResultsDuloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CLss/F), mean apparent volume of distribution (Vss/F) and mean terminal elimination half-life (t½) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and Vss/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval τ at steady state (AUCτ,ss) to the AUC from time zero to infinity after single dosing (AUC∞single dose) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t½ and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported.ConclusionDuloxetine pharmacokinetics in healthy Chinese subjects given a 60mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60mg were well tolerated by healthy Chinese subjects in this study.

Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.

Abstract Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the &Dgr;DHPG/&Dgr;NE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects’ serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The &Dgr;DHPG/&Dgr;NE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.