No significant effect on the exposure to ethanol, diazepam, or lithium following coadministration with vortioxetine was observed. |
Coadministration of ethanol or diazepam with vortioxetine did not result in significant pharmacodynamic (i.e. psychomotor) effects. |
Coadministration of ethanol, diazepam, or lithium with vortioxetine was generally well tolerated. |
1 Introduction
2 Methods
2.1 Subjects
2.2 Study Designs
Concomitant medication | Evaluation | Subjects | Study design | Treatment | Sampling times | PK/PD measures |
---|---|---|---|---|---|---|
Ethanol | Potential PD drug/drug interaction between vortioxetine and ethanol; potential PK interaction between vortioxetine and ethanol | Healthy adults, 18–45 years; N = 77 | Phase I, single-center, double-blind, randomized, two-parallel group, four-period crossover | Single dose of vortioxetine 20 or 40 mg with or without ethanol 0.6 g/kg | Ethanol: At predose and at 0.5, 1.5, 2.5, 4.5, 6.5, 8.5, 18.5, 24 h postdose Vortioxetine and metabolites: Days 1–6 at predose and at 1, 2, 3, 4, 5.5, 6.5, 7.5, 9.5, 11.5, 13.5, 23.5, 36, 48, 72, 96, 120 h postdose | PK: AUClast, AUC∞, C
max, t
max, t
½
PD: attention, working memory, secondary episodic memory, skilled coordination, mood and alertness, postural stability |
Diazepam | Effect of multiple doses of vortioxetine on the PK and PD of a single dose of diazepam | Healthy adults, 19–45 years; N = 54 | Phase I, single-center, double-blind, randomized, placebo-controlled, two-sequence, two-period crossover | Vortioxetine 10 mg or placebo qd for 21 days with diazepam 10 mg administered on day 15 | Diazepam and metabolite: Day 15 at predose and at 0.5, 1, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120, 132, 144, 156,168 h postdose Vortioxetine and metabolites: At predose on days 11–13 and beginning on day 14 at predose and at 1, 3, 4, 6, 8, 10, 12, 16, 24 h postdose | PK: AUClast, AUC∞, AUC24, C
max, t
max, t
½, CL/F, Vz/F
PD: Attention, working memory, secondary episodic memory, attention/psychophysiological threshold, mood and alertness, postural stability |
Lithium | Effect of multiple doses of vortioxetine on the steady-state PK of lithium | Healthy males, 18–45 years; N = 18 | Phase I, single-blind, single-center, single-sequence | Lithium 450 mg ER bid plus vortioxetine placebo qd for 14 days, then lithium 450 mg bid plus vortioxetine 10 mg qd for 14 days | Lithium plasma: At predose on days 11, 12, 13, 25, 26, 27, and at predose and at 1, 2, 4, 6, 8, 10, 12 h post-morning dose on days 14, 28 Lithium urine: At 0–12 h prior to predose day 1 and at 0–12 h post-morning dose on days 14, 28 Vortioxetine: At predose on days 25, 26, 27, and at predose and at 1, 2, 4, 6, 8, 10, 12, 24 h postdose on day 28 | PK: AUC12, C
max, C
min, t
max, Ae12, CLR, F
e
PD: NA |
2.2.1 Ethanol Study
2.2.2 Diazepam Study
2.2.3 Lithium Study
2.3 Bioanalytical
2.3.1 Vortioxetine and Metabolites
2.3.2 Interacting Drugs and Metabolites
2.4 Safety
2.5 Statistical Analysis
3 Results
3.1 Subjects
Ethanol study | Diazepam study | Lithium study | ||
---|---|---|---|---|
Vortioxetine 20 mg (n = 45) | Vortioxetine 40 mg (n = 32) | All subjects (N = 54) | All subjects (N = 18) | |
Sex [n (%)] | ||||
Male | 26 (58) | 32 (100) | 39 (72) | 18 (100) |
Female | 19 (42) | 0 | 15 (28) | 0 |
Age [years; mean (SD)] | 25.7 (5.2) | 30.7 (7.8) | 28.3 (7.9) | 33.2 (6.3) |
Ethnicity [n (%)] | NR | NR | ||
Hispanic/latino | 6 (11) | 15 (83) | ||
Non-hispanic/latino | 48 (89) | 3 (17) | ||
Race [n (%)] | ||||
Black | 0 | 1 (3) | 6 (11) | 4 (22) |
White | 45 (100) | 31 (97) | 48 (89) | 14 (78) |
Weight [kg; mean (SD)] | 74.3 (11.7) | 77.7 (8.8) | 79.3 (13.3) | 175.6 (7.7) |
Height [cm; mean (SD)] | 174.4 (9.6) | 178.3 (6.3) | 175.0 (9.9) | 77.7 (6.1) |
BMI [kg/m2; mean (SD)] | 24.4 (2.7) | 24.4 (2.3) | 25.8 (2.8) | 25.3 (1.9) |
3.2 Ethanol Study
3.2.1 Pharmacokinetics
LS mean | Ratio of LS means [test/reference] (%) | 90 % CI for ratio of LS means (%) | ||
---|---|---|---|---|
Reference | Test | |||
Group 1 | Vortioxetine 20 mg + placebo (n = 36) | Vortioxetine 20 mg + ethanol (n = 38) | ||
AUClast (ng·h/mL) | 476.96 | 474.66 | 99.52 | 94.96–104.30 |
C
max (ng/mL) | 8.97 | 9.26 | 103.23 | 97.38–109.43 |
t
max (h)a
| 7.0 | 7.0 |
Group 2 | Vortioxetine 40 mg + placebo (n = 30) | Vortioxetine 40 mg + ethanol (n = 30) | ||
---|---|---|---|---|
AUClast (ng·h/mL) | 880.77 | 939.17 | 106.63 | 103.09–110.29 |
C
max (ng/mL) | 16.44 | 17.79 | 108.25 | 103.57–113.14 |
t
max (h)a
| 7.0 | 7.0 |
LS mean | Ratio of LS means [test/reference] (%) | 90 % CI for ratio of LS means (%) | ||
---|---|---|---|---|
Reference | Test | |||
Group 1 | Vortioxetine 20 mg + placebo (n = 35) | Vortioxetine 20 mg + ethanol (n = 38) | ||
AUClast (ng·h/mL) | 2378.04 | 2354.47 | 99.01 | 95.08–103.10 |
C
max (ng/mL) | 785.83 | 788.54 | 100.34 | 97.63–103.14 |
t
max (h)a
| 1.5 | 1.5 |
Group 2 | Vortioxetine 40 mg + placebo (n = 30) | Vortioxetine 40 mg + ethanol (n = 30) | ||
---|---|---|---|---|
AUClast (ng·h/mL) | 2524.13 | 2354.46 | 93.28 | 88.54–98.27 |
C
max (ng/mL) | 789.11 | 748.94 | 94.91 | 91.86–98.06 |
t
max (h)a
| 1.5 | 1.5 |
3.2.2 Pharmacodynamics
3.3 Diazepam Study
3.3.1 Pharmacokinetics
LS mean | Ratio of LS means [test/reference] (%) | 90 % CI for ratio of LS means (%) | ||
---|---|---|---|---|
Reference | Test | |||
Diazepam | Placebo + diazepam (n = 33) | Vortioxetine 10 mg + diazepam (n = 34) | ||
AUClast (ng·h/mL) | 5569.24 | 5843.41 | 104.92 | 102.97–106.91 |
C
max (ng/mL) | 243.89 | 231.53 | 94.93 | 87.89–102.54 |
t
max (h)a
| 1.0b
| 1.0b
|
N-desmethyldiazepam | Placebo + diazepam (n = 31) | Vortioxetine 10 mg + diazepam (n = 29) | ||
---|---|---|---|---|
AUClast (ng·h/mL) | 4473.28 | 4663.56 | 104.25 | 101.85–106.71 |
C
max (ng/mL) | 35.05 | 36.36 | 103.72 | 100.98–106.54 |
t
max (h)a
| 131.97c
| 131.99c
|
3.3.2 Pharmacodynamics
3.4 Lithium Study
3.4.1 Pharmacokinetics
LS mean | Ratio of LS means [test/reference] (%) | 90 % CI for ratio of LS means (%) | ||
---|---|---|---|---|
Reference | Test | |||
Placebo + lithium (n = 16) | Vortioxetine + lithium (n = 13) | |||
AUC12 (ng·h/mL) | 46,659.51 | 47,867.43 | 102.59 | 95.26–110.48 |
C
max (ng/mL) | 4705.80 | 4822.64 | 102.48 | 95.85–109.58 |
C
min (ng/mL) | 2949.66 | 2961.21 | 100.39 | 91.02–110.73 |
t
max (h)a
| 4.0b
| 4.0 |