1. EFFECTS OF DULOXETINE ON THE PHARMACOKINETICS OF NEBIVOLOL IN HEALTHY VOLUNTEERS Corina Briciu 1, Maria Neag 2, Dana Muntean 3, Corina Bocsan 2, Anca Buzoianu 2, Ana-Maria Gheldiu 3, Marcela Achim 3, Adina Popa 1, Laurian Vlase 3 University of Medicine and Pharmacy „Iuliu Hatieganu” Cluj-Napoca 1 Department of Clinical Pharmacy, Faculty of Pharmacy 2 Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine 3 Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy 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. 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. 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. Twenty-three, healthy, nonsmoking caucasian males and females, aged 20-35 years took part in the study. Study plan 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 Twenty-three, healthy, nonsmoking caucasian males and females, aged 20-35 years took part in the study. Study plan 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 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. Pharmacokinetics 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) Pharmacokinetics 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 + duloxetine P* value, ANOVA C max (ng/mL)1.78 ±1.171.95 ± 1.190.249438, NS t max (h)1.37 ± 0.881.46 ± 0.850.508795, NS AUC 0-t (ng*h/mL)12.09 ± 24.5115.61 ± 32.870.003029, S AUC 0-∞ (ng*h/mL)17.26 ± 43.0620.57 ± 47.590.004256, S k el (L/h)0.25 ± 0.300.20 ± 0.230.134513, NS t ½ (h)6.65 ± 8.557.45 ± 6.610.134513, NS PK parameters OH-Nebivolol + duloxetine P* value, ANOVA C max (ng/mL)0.58 ± 0.210.83 ± 0.290.000033, S t max (h)3.11 ± 1.762.87 ± 1.350.764337, NS AUC 0-t (ng*h/mL)8.22 ± 7.0111.28 ± 8.000.001135, S AUC 0-∞ (ng*h/mL)13.03 ± 11.2918.60 ± 12.760.001225, S k el (L/h)0.09 ± 0.080.07 ± 0.070.043636, S t ½ (h)16.93 ± 15.4425.50 ± 21.040.043636, S A A B B Period 1 (Reference) Day 1nebivolol 5 mg Period 2 (Test) Day 6duloxetine 30 mg, nebivolol 5 mg INTRODUCTION OBJECTIVE MATERIALS AND METHODS RESULTS CONCLUSION This work was supported by CNCS Romania –project PN-II-ID- PCE-2011-3-0731. Pharmacodynamics A A B B 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 (∆). Between the two periods – pre- treatment with duloxetine (4 days, 30-60 mg/day)  Single-center, open-label, non- randomized, 2-period drug-drug interaction study