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Multiple dose pharmacokinetics of sertraline in subjects with varying degrees of renal impairment
P Poster Presentations binding were observed between the two groups. There were no serious or untoward adverse effects observed in this study. The results of this study indicate that at the same dose level patients with hepatic impairment will have greater exposure to sertraline than would subjects with normal hepatic function. Consequently, if sertraline is administer~d to patients with liver disease, a lower or less frequent dose of sertraline should be used.
I P-2-19I Multiple DosePharmacokinetics of Sertraline in SUbjects with Varying Degrees of Renal Impairment Keith D. Wilner, Barbara A. Baris, George H. Foulds, Rich J. Anziano, Thomas Berl, Michael G. Ziegler. Departmentof Clinical Research,
PfizerCentral Research, Groton, CT, USA; University of Colorado Health Sciences Center, Denver, CO, USA; University of California Medical Center, San Diego, CA, USA The multiple dose pharmacokinetics of sertraline in renal impairment was evaluated in this study. A total of forty-two subjects completed the study and were classified into the following four groups: group I - subjects with creatinine clearance (CLCR) > 70 ml/min (N = 12), group 2 subjects with mild renal impairment (CLCR between 30 and 60 ml/min), inclusive (N = 10), group 3 - subjects with moderate-to-severe renal impairment (CLCR between 10 and 29 ml/min), inclusive (N = 10) and group 4 - subjects requiring regular hemodialysis (3 times/week) (N = 10). All subjects were administered sertraline, once daily starting with 50 mg, titrated with 50 mg increments every 3 days until a maximum dose of 200 mg was obtained. Subjects continued on the 200 mg dose for an additional 21 days regardless of renal function. Steady state was generally obtained after 12 days of 200 mg dosing. After 21 days multiple dosing with 200 mg, there were no statistically significant differences in the AUCO-24 or Cmax among the 4 groups. Half-lives were similar across all groups (means ranging from 24.9 to 31.6 hours). Additionally, there were no differences in plasma protein binding among the four groups. There were no serious or untoward adverse events observed in this study. The results of this study indicate that, as expected from the low renal excretion of sertraline, sertraline dosing would not have to be adjusted based on the degree of renal impairment.
I P-2-20 I Safetyand Pharmacokinetics of Sertraline in Japanese Subjects K. Kamijima , H. Miyaoka, A. Iwanami, C. Tadokoro, T. Otsubo, S. Oyamada. Showa University, School of Medicine
Sertraline Hcl is an antidepressant and one of serotonin re-uptake inhibitors (SSRI). The pharmacokinetics and safety of sertraline Hcl were investigated in a single dose (50, 100 and 200 mg) and multi~le ?os~s (100 mg daily for 10 days) studies and effect of meal on the kI.netlcs. In a Phase I study, all in normal healthy Japanese volunteers. Imipramine Hel was used as a control. The results of the studies were nearly in agreement with those of the studies done in the U.S. in such paramet~rs as Tmax, Cmax and T Sertraline after either single or multiple dosing was slowly absorbed and reached Tmax at 7 hours after dosing with Tmax of about 22 "" 23. Cmax in the 50 mg, 100 mgand 200 mg dose groups were 15.1, 35.7 and 90.8 ng/ml, respectively, demonstrating almost dose-dependency. When a dose of 100 mg daily was administered consecutively for 10 days, the blood concentration reached a steady state by day 4"" 7. Any abnormal changes were not observed in either clinical laboratory tests or physical examination. Marked gastrointestinal side effects such as nausea, vomiting, diarrhea, anorexia, etc. which are common to SSRI were observed but disappeared later. In those given 100 mg of imipramine, marked drowsiness was noted. In the psychological work tests, no decreased work efficiency due to the drug was observed in either single or multiple dose group. The foregoing results suggest that for its long half-life, sertraline exhibits the therapeutic effect for depression with once-a-day dosing. Further, sertraline was judged to be well tolerated at a dose of 100 mg daily or less given repeatedly and to be free of any safety problem which may interfere with subsequent clinical trials.
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I P-2-21 I Pharmacokinetic Profileof Mirtazapine C. Timmer, G. Voortrnan, L. Delbressine. Dept. of Drug Metabolism and Kinetics, NY Organon, Oss, The Netherlands Mirtazapine has a linear pharmacokinetics within dose range of 15-80 mg. It is rapidly and well absorbed from the gastrointestinal tract after single and multiple dosing, and peak plasma levels are reached within 2 hours [I]. The absolute bioavailability is approximately 50% [2]. The presence of food has no effect on the rate and extension of absorption of mirtazapine. It's half life of 20-40 h justifies once daily dosing. Steady-state is achieved within 3-5 days, and approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. The main biotransformation routes are demethylation and oxidation followed by conjugation. The only active metabolite, demethyl-mirtazapine, is shown to be approximately 4-fold less active than the parent compound. As mirtazapine has no inducing or inhibiting effects on the hepatic cytochrome P450 system and its disposition appears to be independent of polymorfic CYP2D6 activity, it has a very low potential for interactions with other drugs, for example with tricyclic antidepressant desipramine or lithium. [I] Timmer et al. Hum Psychopharmacol 1995; 10(suppl 2): S97-SI06 [2] Voortman et al. Hum Psychopharmacoll995; 10 (suppI2): S81-S96
I P-2-22I
Amitriptyline and Nortriptyline: Are Plasma Levels after FirstDosePredictive for Therapeutical Efficacy? C.H. Stuppaeck, A.B. Whitworth, w.w. Fleischhacker. Dept. of Psychiatry, Innsbruck. Austria In a 3-armed, double-blind, double-dummy study design, we tested the hypothesis, that oral treatment of amitriptyline is equally efficient as intravenous application in the treatment of major depression. 90 patients entered the study and received amitriptyline, either 150 mg orally, 100 mg or 150 mg intravenously. The Hamilton Depression Scale, Clinical Global Impression, a self rating adjective checklist (Von Zerssen) and a visual analogue scale were used for the assessment of efficacy. A trend towards an earlier onset of action was shown for the group receiving 150 mg amitriptyline intravenously. We also determined plasma levels of amitriptyline and nortriptyline. Results with 60 patients did not show a correlation between plasma levels after the first dose and therapeutic efficacy or the onset of treatment response.
I P-2-23I Clomipramine and Obsessive-Compulsive Disorder: Serum Levels and Outcome C. Gorenstein, T. Marcourakis, M. Bernik, F. Lotufo-Neto. lnstituto de
Ciencias Biomedicas; Centro de lnvestigacoes em Neurologia; Instituto de Psiquiatria, US?, LlM-23, sao Paulo, Brazil Clomipramine (CMI) has been the reference drug for obsessive-compulsive disorder (OCD). The relationship between plasma concentrations of CMI and its desmethyl metabolite (DCMI) and outcome is not clear, although has been investigated in a number of studies. A single-blind, flexible dose trial, was undertaken to evaluate the relationship between serum levels of CMI and DCMI and clinical effect in 22 patients with obsessive-compulsive disorder as defined by DSM-III-R. The patients were treated for 12 weeks, serum levels and clinical condition were evaluated at weeks 0 (baseline), 3, 6, 8,10 and 12. At the end of the trial 43% of the patients were free of symptoms and mean dose ± sem at week 12 was 223.5 ± 11.6 mg/day (3.27 ± 0.2 mglkg/day); CMI levels (167.9 ± 15.0 ng/mL); DCMI (256.5 ± 49.8 ng/mL) and total serum levels (424.4 ± 55.6 ng/mL). Serum level data were submitted to repeated- measures analysis of variance considering two groups of clinical improvement. Our results have shown that there was a tendency of association between outcome (Yale-Brown Obsessive-Compulsive Scale (YBOCS) total score, and obsessional subscore) with dose/weight relationship. Patients with more improvement had received lower dose/weight than those with less improvement.
I P-2-19I Multiple DosePharmacokinetics of Sertraline in SUbjects with Varying Degrees of Renal Impairment Keith D. Wilner, Barbara A. Baris, George H. Foulds, Rich J. Anziano, Thomas Berl, Michael G. Ziegler. Departmentof Clinical Research,
PfizerCentral Research, Groton, CT, USA; University of Colorado Health Sciences Center, Denver, CO, USA; University of California Medical Center, San Diego, CA, USA The multiple dose pharmacokinetics of sertraline in renal impairment was evaluated in this study. A total of forty-two subjects completed the study and were classified into the following four groups: group I - subjects with creatinine clearance (CLCR) > 70 ml/min (N = 12), group 2 subjects with mild renal impairment (CLCR between 30 and 60 ml/min), inclusive (N = 10), group 3 - subjects with moderate-to-severe renal impairment (CLCR between 10 and 29 ml/min), inclusive (N = 10) and group 4 - subjects requiring regular hemodialysis (3 times/week) (N = 10). All subjects were administered sertraline, once daily starting with 50 mg, titrated with 50 mg increments every 3 days until a maximum dose of 200 mg was obtained. Subjects continued on the 200 mg dose for an additional 21 days regardless of renal function. Steady state was generally obtained after 12 days of 200 mg dosing. After 21 days multiple dosing with 200 mg, there were no statistically significant differences in the AUCO-24 or Cmax among the 4 groups. Half-lives were similar across all groups (means ranging from 24.9 to 31.6 hours). Additionally, there were no differences in plasma protein binding among the four groups. There were no serious or untoward adverse events observed in this study. The results of this study indicate that, as expected from the low renal excretion of sertraline, sertraline dosing would not have to be adjusted based on the degree of renal impairment.
I P-2-20 I Safetyand Pharmacokinetics of Sertraline in Japanese Subjects K. Kamijima , H. Miyaoka, A. Iwanami, C. Tadokoro, T. Otsubo, S. Oyamada. Showa University, School of Medicine
Sertraline Hcl is an antidepressant and one of serotonin re-uptake inhibitors (SSRI). The pharmacokinetics and safety of sertraline Hcl were investigated in a single dose (50, 100 and 200 mg) and multi~le ?os~s (100 mg daily for 10 days) studies and effect of meal on the kI.netlcs. In a Phase I study, all in normal healthy Japanese volunteers. Imipramine Hel was used as a control. The results of the studies were nearly in agreement with those of the studies done in the U.S. in such paramet~rs as Tmax, Cmax and T Sertraline after either single or multiple dosing was slowly absorbed and reached Tmax at 7 hours after dosing with Tmax of about 22 "" 23. Cmax in the 50 mg, 100 mgand 200 mg dose groups were 15.1, 35.7 and 90.8 ng/ml, respectively, demonstrating almost dose-dependency. When a dose of 100 mg daily was administered consecutively for 10 days, the blood concentration reached a steady state by day 4"" 7. Any abnormal changes were not observed in either clinical laboratory tests or physical examination. Marked gastrointestinal side effects such as nausea, vomiting, diarrhea, anorexia, etc. which are common to SSRI were observed but disappeared later. In those given 100 mg of imipramine, marked drowsiness was noted. In the psychological work tests, no decreased work efficiency due to the drug was observed in either single or multiple dose group. The foregoing results suggest that for its long half-life, sertraline exhibits the therapeutic effect for depression with once-a-day dosing. Further, sertraline was judged to be well tolerated at a dose of 100 mg daily or less given repeatedly and to be free of any safety problem which may interfere with subsequent clinical trials.
*'
41
I P-2-21 I Pharmacokinetic Profileof Mirtazapine C. Timmer, G. Voortrnan, L. Delbressine. Dept. of Drug Metabolism and Kinetics, NY Organon, Oss, The Netherlands Mirtazapine has a linear pharmacokinetics within dose range of 15-80 mg. It is rapidly and well absorbed from the gastrointestinal tract after single and multiple dosing, and peak plasma levels are reached within 2 hours [I]. The absolute bioavailability is approximately 50% [2]. The presence of food has no effect on the rate and extension of absorption of mirtazapine. It's half life of 20-40 h justifies once daily dosing. Steady-state is achieved within 3-5 days, and approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. The main biotransformation routes are demethylation and oxidation followed by conjugation. The only active metabolite, demethyl-mirtazapine, is shown to be approximately 4-fold less active than the parent compound. As mirtazapine has no inducing or inhibiting effects on the hepatic cytochrome P450 system and its disposition appears to be independent of polymorfic CYP2D6 activity, it has a very low potential for interactions with other drugs, for example with tricyclic antidepressant desipramine or lithium. [I] Timmer et al. Hum Psychopharmacol 1995; 10(suppl 2): S97-SI06 [2] Voortman et al. Hum Psychopharmacoll995; 10 (suppI2): S81-S96
I P-2-22I
Amitriptyline and Nortriptyline: Are Plasma Levels after FirstDosePredictive for Therapeutical Efficacy? C.H. Stuppaeck, A.B. Whitworth, w.w. Fleischhacker. Dept. of Psychiatry, Innsbruck. Austria In a 3-armed, double-blind, double-dummy study design, we tested the hypothesis, that oral treatment of amitriptyline is equally efficient as intravenous application in the treatment of major depression. 90 patients entered the study and received amitriptyline, either 150 mg orally, 100 mg or 150 mg intravenously. The Hamilton Depression Scale, Clinical Global Impression, a self rating adjective checklist (Von Zerssen) and a visual analogue scale were used for the assessment of efficacy. A trend towards an earlier onset of action was shown for the group receiving 150 mg amitriptyline intravenously. We also determined plasma levels of amitriptyline and nortriptyline. Results with 60 patients did not show a correlation between plasma levels after the first dose and therapeutic efficacy or the onset of treatment response.
I P-2-23I Clomipramine and Obsessive-Compulsive Disorder: Serum Levels and Outcome C. Gorenstein, T. Marcourakis, M. Bernik, F. Lotufo-Neto. lnstituto de
Ciencias Biomedicas; Centro de lnvestigacoes em Neurologia; Instituto de Psiquiatria, US?, LlM-23, sao Paulo, Brazil Clomipramine (CMI) has been the reference drug for obsessive-compulsive disorder (OCD). The relationship between plasma concentrations of CMI and its desmethyl metabolite (DCMI) and outcome is not clear, although has been investigated in a number of studies. A single-blind, flexible dose trial, was undertaken to evaluate the relationship between serum levels of CMI and DCMI and clinical effect in 22 patients with obsessive-compulsive disorder as defined by DSM-III-R. The patients were treated for 12 weeks, serum levels and clinical condition were evaluated at weeks 0 (baseline), 3, 6, 8,10 and 12. At the end of the trial 43% of the patients were free of symptoms and mean dose ± sem at week 12 was 223.5 ± 11.6 mg/day (3.27 ± 0.2 mglkg/day); CMI levels (167.9 ± 15.0 ng/mL); DCMI (256.5 ± 49.8 ng/mL) and total serum levels (424.4 ± 55.6 ng/mL). Serum level data were submitted to repeated- measures analysis of variance considering two groups of clinical improvement. Our results have shown that there was a tendency of association between outcome (Yale-Brown Obsessive-Compulsive Scale (YBOCS) total score, and obsessional subscore) with dose/weight relationship. Patients with more improvement had received lower dose/weight than those with less improvement.