- Email: [email protected]
P-2-76 Effect of lorazepam on the pharmacokinetics of reboxetine in healthy volunteers
300
P-2 Antidepressants." basic and clinical studies
high: 91.7% for paroxetme, 75% for fluvoxamine and 90.5% for fluoxetine When the concordance rate between drugs was considered, a dramatic decrease emerged: 40% between paroxet~ne and fluvoxamine, 58.3% between paroxetine and fluoxetine, 61 1 % between fluvoxamine and fluoxe tine. A further dramatic decrease in the concordance rate resulted when the three SSRIs were considered together: concordant positive or negative responses were 20% (10% of positive response to the three drugs and 10% of negative response to the three drugs), These results seem to suggest that in spite of a supposed similar mechanism of action SSRIs are not a homogeneous class of antidepressants.
of reboxetme with and without Lorazepam was performed using Student t4est for paired data or Wilcoxon non-parametric test at the 5% bevel of significance, Statistical comparison did net reveal any significant difference between reboxetine alone and with Iorazepam concomitant administration. In conclusion, Iorazepam does not affect the pharmacokinetics of reboxetlne. Treatment
C m a x tmax (ng/ml) (h)
AUC{0-t2) AUC tv2 (ng.h/ml) (ng.h/ml) (h)
Ae CLR (% dose) (ml/rnin)
Reboxetine 120±22 1.9:1,1.4 1431:1,198 1855:1,327 151:1,2.4 9.14-4.0 3.954-1.61 Rei3oxetine + Lorazepam 120+20 2.2:1_0.7 1483±269 1752±330 1464-58 694-1.2 2.974-032
References 11] Sacchetti E , Conte G Guarneri L [1994) Are SSRI antidepressants a climcalty homogeneous class of compounds? The Lancet 344, 126-127 (letter)
Dopamine receptor binding in major depression: changes before and after treatment with selective serotonin reuptake inhibitors A. K l i m k e l , R Larisch2, A Janzl, H. Vosberg2 H.W M011er-Gartner 2, W Gaebel 1. 1 Department of Psychiatry, 2 Department of Nuclear
Medicine, University of Duesseldorf, Germany Previous/n v/vo studies demonstrated changes m regional cerebral blood flow and glucose metabolism as well as alterations of the opioid system within the frontal cortex in depression. The present study continues the search for specific biochemical alterations in depression and investigates the potential impact of serotonin reuptake inhibition on the dopaminergic s y s t e m As yet, five patients {age 59.6 4- 9.0 y s mean ± SD, 4 f, 1 m) with major depression were investigated before and immediately following a six week treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetlne (40 mg/d) or fluexetine (up to 60 mg/d) Dopamine receptor binding was estimated using the specific D2 receptor antagonist 1231~odobenzamid (IBZM, 185 Mbq) and SPECT (double head camera PRISM 2000, Picker Ohio) with high resolution collimation. Specific IBZM binding was calculated as the region of interest to cerebellum ratio. The Hamilton Depression Rating Score (HAMD) decreased from 29.4 ± 5 2 before 120 4- 8 3 after treatment, the SANS (Scale of Assessment o ~ Negative Symptoms) total score from 684 4- 26 8 before to 35.8 4- 240 after treatment In the frontal lobe, the averagelBZM binding decreasedbv 11% from 1 16 ± 004 before to 1 03 ± 0.11 after treatment, whereas in the basal ganglia the average IBZM binding remained unchanged. These preliminary data of an ongoing prospective study suggest an mteracuon of the serotonergic with the dopaminergic system in the frontal lobe in major depression Clinical improvement of depressive symptoms might be associated with a decrease of IBZM binding to D2 receptors corresponding to an increase in synaptic dopamlne concentration or a downregulation of dopamine receptors
Effect of Iorazepam on the pharmacokinetics of reboxetine in healthy volunteers F. Fiorentini. I Poggesi, M G. Jannuzzo. M Seiberlingl,R Dostert, M Strolin Benedetti Pharmacia, ROD Pharmacekinet/cs and Metabohsrn~
Nerv/ano MI, Ita/y; 1 fnnovex (Btedesign) GmbH, Freiburg, Germany Reboxetine, (2RS,c~RS)-2-[c~-(2-ethoxyphenoxy)benzylJmorpholine methanesulphonate, is a new prombsin 9 antPdepressant agent currently undergoing clinical evaluation. The aim of this study was to investigate a possible ef fect of multiple dosing of a short-acting tranquillizer of the benzodiazepme group (Iorazepaml on reboxetine pharmacokinet~cs. Six healthy male volunteers (age 26-30 y, weight 72.8-88.5 kg) were enrolled in the study, On day 1, they received a single oral dose of 4 mg reboxetine as a tablet afte~ an overnight fast. Blood and urine samples were collected up to 60 h to be assayed for unchanged reboxetine. Then, Iorazepam (2 x 1 mg/day, as tablets) was given from day 8 t o day 14 On day 151orazepam (1 rag) and reboxetine (4 mg) were given concomitantly after an overnight fast. Blood and urine samples were collected again up to 60 h. Unchanged reboxetine was assayed using an HPLC/UV method. Pharmacokinetic parameters were evaluated using standard non-compartmental methods. No clinically relevant alterations (pulse rate, blood pressure, ECG and climcat laboratory parameters) were observed throughout the study. The most relevant pharmacokinetic parameters (mean 4- SD) are summarized in the followlog table. The statistical comoanson of the pharmacokinetic parameters
Pharmacokinetics of reboxetine in healthy volunteers of different ages M.G Jannuzzo. M. Ryde 1 B. Karlmark 2, O. Ronn 1, C. Pellizzoni, I Poggesi, M. Rocchetti, E. Frigerio, P Dostert, M. Strolin Benedetti.
1 PharmacJa, ROD Pharmacoklnetlcs and Metabohsm, Mi/an, Italy, 1 Pharmacla, Human Pharmacology Unit, University Hospital, Uppsala, Sweden; 2 Med/cingruppen AB, Balders v~g 7A, Uppsa/a, Sweden Reboxetine (RBX) is a new antidepressant agent currently undergoing Phase III clinical trials, Plasma and urine kinetics of RBX have been determined in 5 studies (a, b, c, d, e) in young subjects, in one study (f) in very elderly subjects and in one study (g)in middle-aged and elderly subjects (Table 1) following single oral doses ranging from 1.98 to 4.15 mg RBX as free base. The 95% confidence intervals on arithmetic means of RBX plasma (Cmax, Tmax, tl/2, A U C o ~ ) and renal (Ae %. CLR) pharmacokinetic parameters have been calculated in the above studies, Cmax and A U C 0 ~ had been previously corrected for the close of 4 mg free base RBX. A qualitative comparison based on the 95% confidence intervals indicated no differences in RBX plasma and renal pharmacokinetic parameters between middle-aged and elderly subjects of study g and young subjects of studies a, b, c, d, e. In contrast, differences were evident in both RBX plasma (with exception of Tmax) and renal pharmacokinetic parameters between subjects of study f and the young subjects of studies a, b, c, d, e. Between middle-aged and elderly subjects of study g and the more elderly subjects of study f differences appeared only in RBX plasma pharmacokinetic parameters, The studies performed in young subjects and previous in vitro measurements of RBX binding to plasma proteins indicated that RBX is eliminated in urine mainly by glomerular filtration. Assuming that this mechanism is preserved in elderly, age-related reduction in creatinine clearance (CLcR) may explain only partially the values of pharmacokinetic parameters observed in studies g and f, and other factors (such as the fraction of unbound drug in plasma, bioavailability, metabolic clearance, etc.) should be considered. Study
No. of subj., sex
Age (y)
CL~R mean ± SD (ml/min)
CLR 95% conf. int. (mllmin)
AUC0_= 95% conf. int. (ng.h/ml)
a b c d e f g
15 M 12 M 12M 9M 6M 12 (4 M, 8F) 10 (3 M, 7F) 9 (3 M, 6F)
21 39 20-32 22-36 21-28 26-30 66-98 50~63 68-77
122 4:19 94:1, 14 128±29 95:1, 13 107:1,11 53 4- 28 115:1,23 104:1,20
23-3.6 22 3.6 2 1~t.8 234.7 23-5.6 0 1 0.9 09-23 0.2-3.2
1651- 2646 1734- 2796 1534- 2488 2051- 3360 1558- 2266 6322-10240 2046- 3683 2126- 2993
• normalized to 173 m2.
Effect of reboxetine on the pharmacokinetics of Iorazepam in healthy volunteers M G. Jannuzzo, M. Bosc 1. A. Renoux 2. R Dostert, M. Strolin Benedetti.
Pharmacta, ROD Pharmacokinetics and Metabohsm, M#an, Italy; 1 Pharmacta, Guyancourt, France," 2 Cephac Research Centre, Poitier, France Reboxetine (RBX) is a new antidepressant agent currently undergoing Phase Ill clinical evaluation. The effect of RBX on the pharmacokinetics of Iorazepam (LR) was investigated in 6 healthy mate volunteers (age 20-27,1,, weight 71-90 kg}. On day 1 the volunteers were given a single oral dose of 2 5 mg of LR after an overnight fast From d a y 8 to day 14 they received a multiple dosage regimen of RBX (2x2 mg/day) and on day 15 LR 2.5 mg plus RBX 2 mg after an overnight fast.
P-2 Antidepressants." basic and clinical studies
high: 91.7% for paroxetme, 75% for fluvoxamine and 90.5% for fluoxetine When the concordance rate between drugs was considered, a dramatic decrease emerged: 40% between paroxet~ne and fluvoxamine, 58.3% between paroxetine and fluoxetine, 61 1 % between fluvoxamine and fluoxe tine. A further dramatic decrease in the concordance rate resulted when the three SSRIs were considered together: concordant positive or negative responses were 20% (10% of positive response to the three drugs and 10% of negative response to the three drugs), These results seem to suggest that in spite of a supposed similar mechanism of action SSRIs are not a homogeneous class of antidepressants.
of reboxetme with and without Lorazepam was performed using Student t4est for paired data or Wilcoxon non-parametric test at the 5% bevel of significance, Statistical comparison did net reveal any significant difference between reboxetine alone and with Iorazepam concomitant administration. In conclusion, Iorazepam does not affect the pharmacokinetics of reboxetlne. Treatment
C m a x tmax (ng/ml) (h)
AUC{0-t2) AUC tv2 (ng.h/ml) (ng.h/ml) (h)
Ae CLR (% dose) (ml/rnin)
Reboxetine 120±22 1.9:1,1.4 1431:1,198 1855:1,327 151:1,2.4 9.14-4.0 3.954-1.61 Rei3oxetine + Lorazepam 120+20 2.2:1_0.7 1483±269 1752±330 1464-58 694-1.2 2.974-032
References 11] Sacchetti E , Conte G Guarneri L [1994) Are SSRI antidepressants a climcalty homogeneous class of compounds? The Lancet 344, 126-127 (letter)
Dopamine receptor binding in major depression: changes before and after treatment with selective serotonin reuptake inhibitors A. K l i m k e l , R Larisch2, A Janzl, H. Vosberg2 H.W M011er-Gartner 2, W Gaebel 1. 1 Department of Psychiatry, 2 Department of Nuclear
Medicine, University of Duesseldorf, Germany Previous/n v/vo studies demonstrated changes m regional cerebral blood flow and glucose metabolism as well as alterations of the opioid system within the frontal cortex in depression. The present study continues the search for specific biochemical alterations in depression and investigates the potential impact of serotonin reuptake inhibition on the dopaminergic s y s t e m As yet, five patients {age 59.6 4- 9.0 y s mean ± SD, 4 f, 1 m) with major depression were investigated before and immediately following a six week treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetlne (40 mg/d) or fluexetine (up to 60 mg/d) Dopamine receptor binding was estimated using the specific D2 receptor antagonist 1231~odobenzamid (IBZM, 185 Mbq) and SPECT (double head camera PRISM 2000, Picker Ohio) with high resolution collimation. Specific IBZM binding was calculated as the region of interest to cerebellum ratio. The Hamilton Depression Rating Score (HAMD) decreased from 29.4 ± 5 2 before 120 4- 8 3 after treatment, the SANS (Scale of Assessment o ~ Negative Symptoms) total score from 684 4- 26 8 before to 35.8 4- 240 after treatment In the frontal lobe, the averagelBZM binding decreasedbv 11% from 1 16 ± 004 before to 1 03 ± 0.11 after treatment, whereas in the basal ganglia the average IBZM binding remained unchanged. These preliminary data of an ongoing prospective study suggest an mteracuon of the serotonergic with the dopaminergic system in the frontal lobe in major depression Clinical improvement of depressive symptoms might be associated with a decrease of IBZM binding to D2 receptors corresponding to an increase in synaptic dopamlne concentration or a downregulation of dopamine receptors
Effect of Iorazepam on the pharmacokinetics of reboxetine in healthy volunteers F. Fiorentini. I Poggesi, M G. Jannuzzo. M Seiberlingl,R Dostert, M Strolin Benedetti Pharmacia, ROD Pharmacekinet/cs and Metabohsrn~
Nerv/ano MI, Ita/y; 1 fnnovex (Btedesign) GmbH, Freiburg, Germany Reboxetine, (2RS,c~RS)-2-[c~-(2-ethoxyphenoxy)benzylJmorpholine methanesulphonate, is a new prombsin 9 antPdepressant agent currently undergoing clinical evaluation. The aim of this study was to investigate a possible ef fect of multiple dosing of a short-acting tranquillizer of the benzodiazepme group (Iorazepaml on reboxetine pharmacokinet~cs. Six healthy male volunteers (age 26-30 y, weight 72.8-88.5 kg) were enrolled in the study, On day 1, they received a single oral dose of 4 mg reboxetine as a tablet afte~ an overnight fast. Blood and urine samples were collected up to 60 h to be assayed for unchanged reboxetine. Then, Iorazepam (2 x 1 mg/day, as tablets) was given from day 8 t o day 14 On day 151orazepam (1 rag) and reboxetine (4 mg) were given concomitantly after an overnight fast. Blood and urine samples were collected again up to 60 h. Unchanged reboxetine was assayed using an HPLC/UV method. Pharmacokinetic parameters were evaluated using standard non-compartmental methods. No clinically relevant alterations (pulse rate, blood pressure, ECG and climcat laboratory parameters) were observed throughout the study. The most relevant pharmacokinetic parameters (mean 4- SD) are summarized in the followlog table. The statistical comoanson of the pharmacokinetic parameters
Pharmacokinetics of reboxetine in healthy volunteers of different ages M.G Jannuzzo. M. Ryde 1 B. Karlmark 2, O. Ronn 1, C. Pellizzoni, I Poggesi, M. Rocchetti, E. Frigerio, P Dostert, M. Strolin Benedetti.
1 PharmacJa, ROD Pharmacoklnetlcs and Metabohsm, Mi/an, Italy, 1 Pharmacla, Human Pharmacology Unit, University Hospital, Uppsala, Sweden; 2 Med/cingruppen AB, Balders v~g 7A, Uppsa/a, Sweden Reboxetine (RBX) is a new antidepressant agent currently undergoing Phase III clinical trials, Plasma and urine kinetics of RBX have been determined in 5 studies (a, b, c, d, e) in young subjects, in one study (f) in very elderly subjects and in one study (g)in middle-aged and elderly subjects (Table 1) following single oral doses ranging from 1.98 to 4.15 mg RBX as free base. The 95% confidence intervals on arithmetic means of RBX plasma (Cmax, Tmax, tl/2, A U C o ~ ) and renal (Ae %. CLR) pharmacokinetic parameters have been calculated in the above studies, Cmax and A U C 0 ~ had been previously corrected for the close of 4 mg free base RBX. A qualitative comparison based on the 95% confidence intervals indicated no differences in RBX plasma and renal pharmacokinetic parameters between middle-aged and elderly subjects of study g and young subjects of studies a, b, c, d, e. In contrast, differences were evident in both RBX plasma (with exception of Tmax) and renal pharmacokinetic parameters between subjects of study f and the young subjects of studies a, b, c, d, e. Between middle-aged and elderly subjects of study g and the more elderly subjects of study f differences appeared only in RBX plasma pharmacokinetic parameters, The studies performed in young subjects and previous in vitro measurements of RBX binding to plasma proteins indicated that RBX is eliminated in urine mainly by glomerular filtration. Assuming that this mechanism is preserved in elderly, age-related reduction in creatinine clearance (CLcR) may explain only partially the values of pharmacokinetic parameters observed in studies g and f, and other factors (such as the fraction of unbound drug in plasma, bioavailability, metabolic clearance, etc.) should be considered. Study
No. of subj., sex
Age (y)
CL~R mean ± SD (ml/min)
CLR 95% conf. int. (mllmin)
AUC0_= 95% conf. int. (ng.h/ml)
a b c d e f g
15 M 12 M 12M 9M 6M 12 (4 M, 8F) 10 (3 M, 7F) 9 (3 M, 6F)
21 39 20-32 22-36 21-28 26-30 66-98 50~63 68-77
122 4:19 94:1, 14 128±29 95:1, 13 107:1,11 53 4- 28 115:1,23 104:1,20
23-3.6 22 3.6 2 1~t.8 234.7 23-5.6 0 1 0.9 09-23 0.2-3.2
1651- 2646 1734- 2796 1534- 2488 2051- 3360 1558- 2266 6322-10240 2046- 3683 2126- 2993
• normalized to 173 m2.
Effect of reboxetine on the pharmacokinetics of Iorazepam in healthy volunteers M G. Jannuzzo, M. Bosc 1. A. Renoux 2. R Dostert, M. Strolin Benedetti.
Pharmacta, ROD Pharmacokinetics and Metabohsm, M#an, Italy; 1 Pharmacta, Guyancourt, France," 2 Cephac Research Centre, Poitier, France Reboxetine (RBX) is a new antidepressant agent currently undergoing Phase Ill clinical evaluation. The effect of RBX on the pharmacokinetics of Iorazepam (LR) was investigated in 6 healthy mate volunteers (age 20-27,1,, weight 71-90 kg}. On day 1 the volunteers were given a single oral dose of 2 5 mg of LR after an overnight fast From d a y 8 to day 14 they received a multiple dosage regimen of RBX (2x2 mg/day) and on day 15 LR 2.5 mg plus RBX 2 mg after an overnight fast.