Transcript Pharmacokinetics

EFFECTS OF DULOXETINE ON THE PHARMACOKINETICS OF NEBIVOLOL IN
HEALTHY VOLUNTEERS
Corina Briciu1, Maria Neag2, Dana Muntean3, Corina Bocsan2, Anca Buzoianu2, Ana-Maria Gheldiu3, Marcela Achim3, Adina Popa1,
Laurian Vlase3
University of Medicine and Pharmacy „Iuliu Hatieganu” Cluj-Napoca
1Department of Clinical Pharmacy, Faculty of Pharmacy
2Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine
3Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy
INTRODUCTION
MATERIALS AND METHODS
Nebivolol is a third-generation beta-blocker indicated for the
management of essential hypertension and chronic heart failure in
elderly pacients. Nebivolol is subject to extensive first-pass metabolism
in the liver via CYP2D6 and produces active β- blocking hydroxylated
metabolites.
Duloxetine is a dual and potent norepinephrine and serotonin-reuptake
inhibitor (SNRI) used to treat disorders like depression, generalized
anxiety disorder or diabetic peripheral neuropathic pain. Duloxetine is a
moderate inhibitor of CYP2D6 activity and as a consequence, this
antidepressant has a much greater potential for clinically important drug
interactions when it is co-administered with CYP2D6 substrates.
OBJECTIVE
To investigate whether a potentially harmfull pharmacokinetic
interaction occurs between nebivolol and duloxetine in healthy
volunteers and to establish whether this drug interaction, if any, affects
the pharmacodynamics of nebivolol in vivo.
2.0
1.0
1
0
6
12
18
24
30
36
42
48
0
Time (h)
0
1.5
1.0
0.5
Concentration (ng/ml)
Concentration
(ng/ml)
2.5
0.9
0.8
0.7
0.6
randomized, 2-period drug-drug
Period 1 (Reference)
interaction study
Day 1 nebivolol 5 mg
Period 2 (Test)
Between the two periods – pretreatment with duloxetine (4
Day 6 duloxetine 30 mg,
days, 30-60 mg/day)
nebivolol 5 mg
Pharmacokinetic analysis
Non-compartmental pharmacokinetic analysis was employed
to determine the PK parameters of nebivolol and its
hydroxylated active metabolite in the two study periods
Pharmacodynamic analysis
The effect of nebivolol on resting vital signs (blood pressure
and heart rate) was evaluated – a graphical and statistical
approach
Pharmacodynamics
B
NEBIVOLOL
1
0
6
0
110
0
Time (h)
0.5
0.4
0.3
0.2
0.1
105
100
90
85
80
75
70
6
12
18
24
30
36
42
48
0
0
6
12
18
24
30
36
42
6
12
48
Time (h)
Time (h)
Mean (±SD) plasma levels of nebivolol (A) and its hydroxylated active
metabolite (B), corresponding to nebivolol administered alone (continuous
line) or in combination with duloxetine (dotted line); In insert: semilogarithmic
presentation.
Pharmacokinetic parameters (PK) (mean ± SD) of nebivolol and its active
metabolite (OH-Nebivolol), before and after treatment with duloxetine and the
results of statistical analysis (*P < 0.05 – statistically significant (S); NS – not significant)
PK
parameters
Nebivolol
Nebivolol
+ duloxetine
P* value,
ANOVA
Cmax (ng/mL)
tmax (h)
AUC0-t (ng*h/mL)
AUC0-∞ (ng*h/mL)
kel (L/h)
t½ (h)
1.78 ±1.17
1.37 ± 0.88
12.09 ± 24.51
17.26 ± 43.06
0.25 ± 0.30
6.65 ± 8.55
1.95 ± 1.19
1.46 ± 0.85
15.61 ± 32.87
20.57 ± 47.59
0.20 ± 0.23
7.45 ± 6.61
0.249438, NS
0.508795, NS
0.003029, S
0.004256, S
0.134513, NS
0.134513, NS
PK
parameters
OH-Nebivolol
OH-Nebivolol
+ duloxetine
P* value,
ANOVA
Cmax (ng/mL)
tmax (h)
AUC0-t (ng*h/mL)
AUC0-∞ (ng*h/mL)
kel (L/h)
t½ (h)
0.58 ± 0.21
3.11 ± 1.76
8.22 ± 7.01
13.03 ± 11.29
0.09 ± 0.08
16.93 ± 15.44
0.83 ± 0.29
2.87 ± 1.35
11.28 ± 8.00
18.60 ± 12.76
0.07 ± 0.07
25.50 ± 21.04
0.000033, S
0.764337, NS
0.001135, S
0.001225, S
0.043636, S
0.043636, S
18
24
30
36
42
48
Time (h)
NEBIVOLOL
NEBIVOLOL+DULOXETINE
110
Resting HR
_relative effect (%)
0
A
95
0.0
0.0
NEBIVOLOL+DULOXETINE
115
12 18 24 30 36 42 48
Resting SBP
_relative effect (%)
10
3.0
Concentration (ng/ml)
Pharmacokinetics
A
Concentration
(ng/ml)
RESULTS
Twenty-three, healthy, nonsmoking caucasian males and
females, aged 20-35 years took part in the study.
Study plan
Single-center, open-label, non-
95
B
80
65
50
0
6
12
18
24
30
36
42
48
Time (h)
Mean ± SD time course of reduction in resting systolic blood
pressure (SBP-A) and resting heart rate (HR-B) in 23 healthy
volunteers after a single oral dose of 5 mg nebivolol before
(□) and after duloxetine treatment (∆).
CONCLUSION
Multiple-dose
duloxetine
influenced
the
pharmacokinetics of nebivolol in healthy volunteers,
increasing its exposure due to enzymatic inhibition,
but the interaction had no significant effect upon
nebivolol pharmacodynamics. Further studies are
required to investigate the clinical significance of this
drug interaction.
This work was supported by CNCS Romania –project PN-II-IDPCE-2011-3-0731.