Pharmacokinetics and Safety of Vortioxetine in the Chinese Population.

INTRODUCTION: Major depressive disorder (MDD) is associated with a significant burden of disease in China. Awareness and better access to treatments could help alleviate the burden associated with MDD. Because variations have been observed in the pharmacokinetics (PK) of antidepressants across different races and ethnicities, evaluation of the clinical pharmacology of vortioxetine in diverse populations remains important to assess the potential need for dose adjustments. METHODS: Data were pooled from two phase I open-label PK studies in healthy Chinese subjects, and one phase III double-blind noninferiority study in Chinese patients with MDD to describe the PK and safety data for vortioxetine. Doses in these studies ranged from 10 mg (single dose) to 10 and 20 mg (multiple daily doses). A population PK analysis of vortioxetine in the Chinese population was conducted using nonlinear mixed-effect modeling. RESULTS: In total, 186 individuals were included in the PK analysis: 79 healthy Chinese subjects and 107 Chinese patients with MDD. No clinically significant differences in the PK of vortioxetine were observed between the Chinese population and the previous data in non-Chinese populations. Because of a generally lower weight in the Chinese population compared with the non-Chinese population, exposures were 19% and 18% higher in the Chinese population than in the non-Chinese population (for maximum observed plasma concentration and area under the plasma concentration-time curve, respectively), which is not considered clinically relevant. A high prevalence of pruritus was observed in one phase I PK study (56% overall); however, this was not reflected in the phase III study in Chinese patients with MDD (0.8%). CONCLUSIONS: The PK parameters of vortioxetine in Chinese subjects were comparable to previous data in non-Chinese subjects. Overall, no new safety concerns were raised among the Chinese population. On the basis of this analysis, the tolerability profile of vortioxetine in Chinese healthy subjects and in patients with MDD is expected to be comparable to that in the non-Chinese population. FUNDING: H. Lundbeck A/S, Valby, Denmark. TRIAL REGISTRATION: NCT01676571.

Vortioxetine: Clinical Pharmacokinetics and Drug Interactions.

Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men.

We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40 mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects.All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine.

Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant.

BACKGROUND AND OBJECTIVE: The identification and quantification of potential drug-drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor). METHODS: The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration-time curve [AUC] and maximum plasma concentration [C max]) was used to assess pharmacokinetic interactions. RESULTS: Co-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5'-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80-125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity. CONCLUSION: Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.

The clinical pharmacokinetics of Lu AA21004 and its major metabolite in healthy young volunteers.

Lu AA21004 is a novel multimodal antidepressant that is currently in phase 3 development. The objective of this report was to detail the clinical pharmacokinetics of Lu AA21004 and its major but inactive metabolite Lu AA34443 (3-methyl-4-(2-piperazine-1-yl-phenylsulfanyl)-benzoic acid) in healthy men and women aged between 18 and 53 years. Data from two single-dose and one multiple-dose study were combined; the total number of volunteers was 97 (64 men, 33 women). Blood and urine samples were collected after p.o. and i.v. administrations to determine the content of Lu AA21004 and Lu AA34443 performed with a validated method. Standard pharmacokinetic parameters were estimated with non-compartmental analysis. The absolute bioavailability was 75%. After oral administration, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution resulting in late t(max) values and a mean elimination half-life of 57 hr. The exposure of Lu AA21004 showed a linear relationship with dose in the dose ranges studied (up to 75-mg single dosing and 60-mg multiple dosing). After weight correction, no differences in exposure for Lu AA21004 and Lu AA34443 were observed between men and women. The renal clearance of Lu AA21004 was negligible. The major metabolite Lu AA34443 had a half-life similar to that of Lu AA21004 but a lower accumulation ratio at steady-state, indicating formation-rate-limited elimination. In conclusion, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution.

Effect of nalmefene 20 and 80 mg on the corrected QT interval and T-wave morphology: a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study.

BACKGROUND: Nalmefene is an orally administered competitive opioid receptor antagonist targeted at reducing alcohol consumption in alcohol-dependent patients. As part of the regulatory requirements for drug approval, the potential of novel compounds for causing unwanted proarrhythmia should be studied in a thoroughly designed clinical QT/corrected QT (QTc) study (International Conference on Harmonisation [ICH] E14 guideline). OBJECTIVE: This study was designed to evaluate whether nalmefene 20 and 80 mg/day induced changes in cardiac repolarization biomarkers indicative of proarrhythmia (the QTc interval and T-wave morphology). METHODS: This was a prospective, randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study carried out in a clinical pharmacology unit. The study included 270 healthy male and female subjects (age 18-45 years). The subjects were randomized to a 7-day treatment period of placebo, nalmefene 20 mg/day or nalmefene 80 mg/day, or placebo for 6 days followed by a single dose of moxifloxacin 400 mg on day 7. Serial triplicate ECGs were obtained over a 24-hour period at protocol-defined time-points. The primary protocol-defined endpoint was the largest time-matched baseline- and placebo-adjusted mean difference in the individually heart rate-corrected QT interval (QTcNi) recorded at any of the 12 ECG time-points distributed over a 24-hour period on day 7 of treatment. Secondary endpoints included a similar analysis using the Fridericia- (QTcF) and Bazett-corrected (QTcB) intervals. An explorative analysis included quantitative assessment of T-wave morphology using the T-wave morphology composite score (MCS) to assess for differences between treatment groups and placebo on day 7 of treatment. The frequency of outliers in the QTc intervals, the pharmacokinetics of nalmefene and the tolerability of nalmefene were also assessed. RESULTS: Nalmefene was rapidly absorbed with a time to reach maximum plasma concentration of 2.2 hours and a dose-proportionate relationship between dose administered and exposure. The largest baseline- and placebo-adjusted mean changes from baseline in the individualized QTcNi (primary endpoint) were 5.45 ms (90% CI 1.52, 9.37) and 5.57 ms (90% CI 1.62, 9.52) for nalmefene 20 and 80 mg/day, respectively, with study sensitivity confirmed by the expected largest increase in mean QTcNi of 10.15 ms (90% CI 5.67, 14.63) for moxifloxacin. Quantitative assessment using the T-wave MCS demonstrated the largest baseline- and placebo-adjusted increase in MCS to be non-significantly different from the intra-subject variability of triplicate recordings in the placebo group. No deaths or serious adverse events occurred in the study. CONCLUSION: This thorough QT/QTc study was a negative study in accordance with the ICH E14 guideline, meaning that nalmefene has no clinically relevant effect on the QTc interval and T-wave morphology. The study predicts no concern over proarrhythmia or need for intensive QTc monitoring with the use of nalmefene in clinical practice.