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PHARMACOKINETICS AND PHARMACODYNAMICS |
From DOV Pharmaceutical, Inc, Hackensack, New Jersey.
Address for reprints: P. Skolnick, DOV Pharmaceutical, Inc, Continental Plaza, 433 Hackensack Avenue, Hackensack, NJ 07601.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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of DOV 216,303 following 1 and 10 days of dosing. The present results demonstrate that DOV 216,303 is safe and well tolerated both at single doses of up to 100 mg and multiple doses of up to 100 mg/day for 10 days. Plasma concentrations of DOV 216,303 after doses > 10 mg exceed its reported IC50 values for inhibition of biogenic amine reuptake.
Key Words: DOV 216,303 • antidepressives • triple reuptake inhibitors • drug safety • pharmacokinetics
3 or more weeks in most double-blind, placebo-controlled trials) to effect a significant improvement in depressive symptomatology. Furthermore, a substantial proportion of patients (between 30% and 40% in most double-blind, placebo-controlled trials) do not derive clinically meaningful benefit following either selective reuptake inhibitors or more traditional biogenic amine-based therapies (reviewed by Paul3).
During the past decade, a number of therapeutic strategies have emerged to both accelerate the onset of antidepressant action and increase efficacy. Several of these strategies may be viewed as significant departures from biogenic amine-based therapies,4-6 whereas others are grounded in biogenic amine-based theories of depression.7,8 Among novel biogenic amine-based strategies is the "triple reuptake" inhibitor (also termed a broad-spectrum antidepressant),8 which inhibits the reuptake of norepinephrine, serotonin, and dopamine, the 3 biogenic amines most closely linked to depression.9-11 DOV 216,303 is an azabicyclo[3.1.0]hexane (Figure 1) that inhibits the reuptake of these 3 amines.12 The potency of DOV 216,303 to inhibit the reuptake of these amines (IC50 values range from 
14-78 nM; see Skolnick et al12) is within the range reported for clinically useful antidepressants.13 Furthermore, DOV 216,303 is active in the forced swim test (minimum effective dose in mice, 10 mg/kg) following oral administration.12 Activity in this preclinical procedure is considered predictive of an antidepressant action in humans.14-16 DOV 216,303 was also orally available in both rats and dogs. Following single doses, plasma concentrations of DOV 216,303 increased in proportion with dose in both species. Furthermore, at doses that were safe and well tolerated in rats and dogs (30 mg/kg and 25 mg/kg, respectively), no significant accumulation of DOV 216,303 in plasma was noted following 2 weeks of oral administration (unpublished data). These preclinical findings prompted a first-in-human study with DOV 216,303. Based on the t1/2 of DOV 216,303 (3.3-4.4 hours) in the initial, ascending single-dose study, 2 regimens (2 and 3 times daily) were selected for a 10-day multiple-dose study. In this report, we describe the safety, tolerability, and pharmacokinetic profile of DOV 216,303 in humans.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects
The single- and multiple-dose studies were conducted at the Parexel-CEMAF Clinical Facility (Poitiers, France). Study protocols were approved by an independent institutional review board (Poitou-Charentes, France), and written informed consent was obtained from all volunteers. Study subjects were healthy male volunteers, between 18 and 35 years old, and within 10% of ideal body weight. At the screening visit, volunteers had to be free from any significant abnormality on the basis of medical history, physical examination, and laboratory (including hematology, clinical chemistry, urinalysis, electrocardiogram [ECG], virology, and a "drugs of abuse and addiction" screen) values.
Study Design
Both the single- and multiple-dose studies were randomized, double-blind, placebo-controlled trials to evaluate the safety, tolerability, and pharmacokinetic profile of DOV 216,303. The single-dose study represented a parallel-arm trial investigating 6 dose levels of DOV 216,303 (5, 10, 25, 50, 100, and 150 mg) and placebo in an ascending-dose design. In the multiple-dose study, volunteers received total daily doses of 50 (25 mg bid), 75 (25 mg tid), and 100 (50 mg bid) mg of DOV 216,303 or placebo for 10 days. In both single- and multiple-dose studies, 7 volunteers were assigned to receive DOV 216,303 and 3 to receive placebo at each dose level. One patient in the 100-mg arm dropped out prior to receiving study medication.
Baseline Phase
The following assessments were made within 14 days of dosing: medical history, physical examination, standard hematological analysis, clinical chemistry (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, 
-glutamyl transferase, glucose, bilirubin, uric acid, creatinine, total protein, cholesterol, triglycerides, and electrolytes), urinalysis, urine drug analysis, virology screen (hepatitis B surface antigen, anti-Hbc IgG antibodies, anti-hepatitis C [HCV] antibodies), 12-lead ECG, and vital signs (blood pressure, heart rate, respiratory rate, temperature). Twenty-four hours prior to treatment, volunteers were retested for drugs of abuse in the urine. A standard hematological analysis and clinical chemistry battery were repeated when screening laboratory tests were performed 5 or more days prior to dosing.
Treatment Phase
Single-dose study. Volunteers were confined to the facility for at least 13 hours prior to dosing and remained at the facility for at least 24 hours after dosing. Subjects were fasted overnight for 10 hours prior to receiving the first dose of study medication or placebo. Vital signs were recorded, and 10 mL of blood was drawn for baseline pharmacokinetic measurement prior to the first dose of study medication or placebo. Subjects received test substance between 0800 and 0900 hours with 240 mL of tap water. No food was permitted for 4 hours after drug administration. Blood samples (10 mL) were drawn at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdosing. Vital signs were examined at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdosing. Adverse experiences were monitored throughout the study day and for at least 24 hours postdosing. Prior to discharge, volunteers received a physical examination, standard hematological analysis, clinical chemistry battery, urinalysis, and 12-lead ECG.
Multiple-dose study. Volunteers were confined to the facility for at least 13 hours prior to the first dose and remained at the facility for at least 24 hours after the last dose of DOV 216,303 or placebo. Subjects were fasted overnight (10 hours) prior to receiving the first dose of study medication or placebo. Prior to this first dose, vital signs were recorded, and 10 mL of blood was drawn for baseline pharmacokinetic measurement. Subjects on twice-daily regimens received the morning dose at between 0800 and 0900 hours and the second dose 12 hours later. Subjects receiving drug (or placebo) 3 times a day were administered the midday dose at 1400 hours, with the morning and evening doses at 0800 and 2000 hours, respectively. Capsules were taken with 240 mL of mineral water. Lunch was served at 1200 hours, with no food permitted until then. Evening meals were served at 1700 hours and a light supper at 2000 hours. Vital signs were examined predosing and at 0.5, 1, 2, 4, 8, and 12 hours after the first (morning) dose on days 1 and 10, as well as prior to the first dose on days 2 to 6 of the study. Blood samples (10 mL) were drawn at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 hours after the first dose on days 1 and 10. Adverse experiences were monitored throughout the study day and for at least 24 hours postdosing. Prior to discharge, volunteers received a physical examination, standard hematological analysis, clinical chemistry battery, urinalysis, and 12-lead ECG.
Bioanalytical Methods
Blood samples (10 mL) were collected in Li-heparin-containing tubes. Within 1 hour of sample collection, the tubes were centrifuged at 3000 rpm for 15 minutes at 2°C. The plasma was placed into polypropylene tubes and stored at -20°C until assayed at PAREXELCEMAF Bioanalytical Laboratories (Poitiers, France). Plasma samples were assayed using a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method using DOV 220,075 (bicifadine) as the internal standard (IS). All reagents were analytical grade or better. Plasma samples (0.5 mL) were added to disposable glass tubes along with 250 ng of IS, 4 mL of a pH 9 buffer, and 8 mL of diethyl ether/hexane (1:1). After 15 minutes of shaking and subsequent centrifugation, 6 mL of the organic layer was transferred to a clean tube. The extraction procedure was repeated once; the organic layers were combined and dried under a stream of nitrogen. The extract was resuspended in 0.2 mL of water/methanol (1:1) and transferred to an injection vial. A Waters Alliance system was used for liquid chromatography. The stationary phase of the analytical column (4.6 x 50 mm) was a Hypersil BDS C-18 (3 µM). The mobile phase was acetonitrile/methanol/formic acid/water (30:35:0.5:34.5), and the flow rate was 0.4 mL/min. A PerkinElmer SCIEX API 3000 system operating in the APCI positive mode was used to collect the mass spectra. The following ion transitions were monitored: 227.9 
187.2 for DOV 216,303 and 174.2 133.1 for the IS. The range of the calibration curve was 0.5 to 2000 ng/mL. A 1/X2 weighted quadratic regression analysis was used to plot the curve. The accuracy of both the calibration standards and quality control samples was within 3% of the theoretical values, whereas the precision was 6.9% or less.
Pharmacokinetic Parameters
Pharmacokinetic parameters were estimated from individual plasma concentration versus time profiles using model-independent methods (Pharsight WinNonlin, Version 4.0.1). The peak concentration (Cmax) and time to Cmax (tmax) were directly estimated from plots of plasma concentration versus time. The elimination rate constant (K) was determined by least squares regression analysis of the terminal portion of the (log) plasma concentration versus time plot. The elimination phase half-life (t1/2) was calculated by the quotient 0.693/K. The area under the plasma concentration versus time curve between time zero and the last measurable concentration (AUC0-t) was calculated by the linear trapezoidal method in the ascending portion of the curve and by the logarithmic method in the descending portion of the curve. The AUC for the dosing interval (0-12 hours for bid dosing and 0-6 hours for tid dosing, respectively) was also calculated for days 1 and 10. AUC0-
(area under the curve from time zero to infinity) was estimated by adding AUC0-t and Ct/K (the plasma concentration at the last measurable time point/elimination rate constant). The accumulation ratio was calculated as the AUC of the first dosing period on day 10 divided by the AUC of the first dosing period on day 1.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Analysis of variance was used to investigate the relationship between pharmacokinetic measures and dose of study medication. A linear contrast variable across all dose levels was applied to test dose proportionality. A separate analysis was performed for Cmax and AUC (Table II). In both analyses, a highly significant linear association was obtained between pharmacokinetic measures and medication dose (Cmax: F = 246.8, df = 1, 40, P < .0001; AUC: F = 344.8, df = 1, 40, P < .0001). The linear association accounted for 89% and 92% of the total variance in Cmax and AUC, respectively, indicating that the dose-proportional model provided an adequate fit to the observed data from 5 to 150 mg (Table II, Figure 2). tmax occurred at approximately 1 hour, whereas the mean elimination half-life was 3.3 to 4.4 hours at all 6 dose levels.
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Multiple-Dose Study
Volunteers received 25 mg bid, 25 mg tid, and 50 mg bid of DOV 216,303 or placebo for 10 days. No drug-related effects were observed on vital signs (heart rate, respiratory rate, blood pressure), EEG, ECG, or hematological or clinical chemistry measures (data not shown). Minor adverse events were reported only in the group receiving 50 mg bid: nausea with dyspepsia in 2 individuals, diarrhea (classified as mild), hemorrhoids, and sperm in urine with possible relationship to the study drug (Table III). No laboratory-adverse events were reported during the study.
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Cmax values of DOV 216,303 appeared similar after repeated administration at all 3 dose levels (Figures 3 and 4; Table IV). Analysis of covariance (ANCOVA) was applied to investigate whether data from this multiple-dose study were homogeneous with regard to the linear, dose-proportional model observed following single doses of DOV 216,303. The null hypothesis (ie, the 2 studies are homogeneous with regard to the dose-response association) was tested for 2 periods of interest: (1) the first dose on study day 1 and (2) the first dose on study day 10 (ie, the last day of dosing) using Cmax as the principal dependent variable. Similar to the results obtained in the single-dose trial, ANCOVA analyses indicated that the overall (main) effect of dose on Cmax was highly significant (P < .0001 for both days 1 and 10). The interaction between study duration and dose level was not statistically significant (P > .1 for both the single-dose and the multiple-dose phases). This lack of interaction indicates that multiple dosing of DOV 216,303 did not alter the dose-proportional model derived from the first, single-dose study. The mean tmax values were similar for the first dosing period on days 1 and 10 for all 3 dosing regimens (Table IV). Based on the shape of the plasma concentration versus time curve at 0 to 6 hours and 6 to 12 hours in the tid dosing arm (Figure 4), it can be inferred that a meal may slow the absorption of DOV 216,303. Although a more rigorous investigation will be required to determine the effect of food on the disposition of DOV 216,303, in the present study, the extent of absorption did not appear to be affected by a meal (736 ± 125 vs 762 ± 147 ng•h/mL at 0-6 and 6-12 hours, respectively).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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At the highest single dose used in this study (150 mg), gastrointestinal disturbances (nausea, vomiting, meteorism) were noted in 4 of 7 subjects (Table I). In multiple-dose studies, nausea and diarrhea were reported in 3 of 7 subjects receiving a total daily dose of 100 mg (Table III). In view of the high plasma concentrations of DOV 216,303 following oral administration and its potency to inhibit [3H]serotonin uptake in vitro (IC50 14 nM12), reports of nausea following administration of this compound could be associated with blockade of serotonin reuptake. This conclusion is consistent with reports that nausea is a frequent adverse event produced by both selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), with overall rates as high as 58% (reviewed in Detke et al17).
Drug-related effects on vital signs, including heart rate and blood pressure, were absent (data on file at DOV Pharmaceutical Inc, Hackensack, NJ). At face value, these findings seem inconsistent with a potent (IC50 21 nM) inhibitor of [3H]norepinephrine uptake.12 Cmax values of DOV 216,303 following doses of 10 mg (Tables III, IV; Figures 2, 3, 4) exceed its IC50 to inhibit [3H]norepinephrine uptake by more than 1 order of magnitude, indicating that norepinephrine transporters are fully inhibited. However, the effects of DOV 216,303 on heart rate and blood pressure were measured with volunteers in the sitting position, and an effect on blood pressure and/or heart rate might be evident if these vital signs were taken with volunteers in an upright position. In addition, DOV 216,303 potently inhibits [3H]serotonin and [3H]dopamine (IC50 78 nM12) uptake, actions that may mitigate the expected increases in heart rate and blood pressure following blockade of norepinephrine transporters. Consistent with this hypothesis, at therapeutic doses,17 the SNRI duloxetine did not alter either blood pressure or heart rate (measured in a supine position), whereas the selective norepinephrine reuptake inhibitor, desmethyl-imipramine, significantly increased both measures.18 Similarly, dual-uptake inhibitors either do not affect (duloxetine19) or only very modestly blunt (venlafaxine20) the tyramine pressor response at therapeutic doses.
Two regimens (bid and tid) of DOV 216,303 were used in these multiple-dose studies. Thus, although single doses of up to 100 mg were well tolerated, no information was available on the tolerability of multiple doses. Dividing doses is one strategy that can be employed to minimize potential side effects related to Cmax. Furthermore, a divided dosing regimen also increases the likelihood that drug levels will be sufficient to effect a sustained inhibition of each transporter. Although additional pharmacodynamic studies (eg, brain imaging, measurement of urinary catecholamine metabolites) will be needed to optimize the dosing regimen of DOV 216,303, the advantage of divided dosing for antidepressants has been questioned, even for compounds with relatively short half-lives.17,21 Based on the safety, tolerability, and pharmacokinetic data described in this preliminary report, we have initiated a multicentered, double-blind investigation of the safety, efficacy, and tolerability of DOV 216,303 (50 mg, bid) in depressed individuals.
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FOOTNOTES |
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Submitted for publication February 5, 2004; Revised version accepted July 26, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Skolnick P, ed. Antidepressants: New Pharmacological Strategies. Totowa, NJ: Humana Press; 1997.
2. Kent JM. SNaRIs, NASSAs, and NaRIs: new agents for the treatment of depression. Lancet. 2000;355: 911-918.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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4. Rupniak NM, Kramer MS. Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol Sci. 1999;20: 485-490.[CrossRef][Medline] [Order article via Infotrieve]
5. Skolnick P, Legutko B, Li X, Bymaster FP: Current perspectives on the development of non-biogenic amine based antidepressants. Pharmacological Res. 2001;43: 411-423.
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7. Romero L, Casanovas JM, Hervas I, Cortes R, Artigas F. Strategies to optimize the antidepressant action of selective serotonin reuptake inhibitors. In: Skolnick P, ed. Antidepressants: New Pharmacological Strategies. Totowa, NJ: Humana Press; 1997: 1-33.
8. Skolnick P. Antidepressants beyond monoamine-based therapies: clues to new approaches. J Clin Psychiatry. 2002;63: 19-23.
9. D'Aquila PS, Collu M, Gessa GL, Serra G. The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol. 2000;405: 365-373.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Brunello N, Mendlewicz J, Kasper S, et al. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharm. 2002;12: 461-475.[CrossRef][Medline] [Order article via Infotrieve]
11. Willner P. Dopaminergic mechanisms in depression and mania. In: Watson S, ed. Psychopharmacology: The Fourth Generation of Progress. New York: Lippincott Williams & Wilkins; 2000.
12. Skolnick P, Popik P, Janowsky A, Beer B, Lippa A. "Broad spectrum" antidepressants: is more better for the treatment of depression? Life Sci. 2003;73: 3175-3179.[CrossRef][Medline] [Order article via Infotrieve]
13. Eshleman AJ, Carmolli M, Cumbay M, et al. Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. J Pharmacol Exp Ther. 1999;289: 877-885.
14. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229: 327-336.[Web of Science][Medline] [Order article via Infotrieve]
15. Borsini F, Meli A. Is the forced swim test a suitable model for revealing antidepressant activity? Psychopharmacology. 1988;94: 147-160.[Medline] [Order article via Infotrieve]
16. Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci. 2002;23: 238-245.[CrossRef][Medline] [Order article via Infotrieve]
17. Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63: 308-315.[Web of Science][Medline] [Order article via Infotrieve]
18. Chalon SA, Grainer L-A, Vandenhende FR, et al. Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study. Neuropsychopharmacology. 2003;28: 1685-1693.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Chalon S, Bieck PR, Goldstein DJ, Bymaster FP, Potter WZ, Demitrack MA. The tyramine pressor test may have limited sensitivity, especially in the presence of dual serotonin/norepinephrine uptake inhibition. Neuropsychopharmacology. 2002;26: 698-699.[CrossRef][Medline] [Order article via Infotrieve]
20. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry. 2000;57: 503-509.
21. Yyldyz A, Sachs GS. Administration of antidepressants: single versus split dosing: a meta-analysis. J Affect Dis. 2001;66: 199-206.[Medline]
[Order article via Infotrieve]
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