| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PHARMACOKINETICS AND PHARMACODYNAMICS |
From Merck Research Laboratories, Boston, Massachusetts (Dr Addy); Merck Research Laboratories, Rahway, New Jersey (Dr Rothenberg, Dr Yuan, Dr Maes, Dr Dunbar, Ms Cote, Ms Rosko, Dr Gottesdiener, Dr Stoch, Dr Wagner); Merck Research Laboratories, West Point, Pennsylvania (Dr S. Li, Dr Majumdar, Dr Agrawal, Mr H. Li, Dr Zhong); MSD (Europe), Brussels, Belgium (Dr Van Dyck, Dr De Lepeleire); Center for Clinical Pharmacology, University Hospital, Leuven, Belgium (Dr de Hoon, Dr Van Hecken, Dr Depré); and SGS Life Science Services, Antwerp, Belgium (Dr Knops). Paul Rothenberg's current affiliation is Johnson & Johnson, Raritan, New Jersey. Jinyu Yuan's current affiliation is Pfizer, New York, NY. Annemie Knops' current affiliation is CM Limburg, Hasselt, Belgium.
Address for reprints: Carol Addy, MD, MMSc, Director, Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115; e-mail: carol_addy{at}merck.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: MK-0364 • taranabant • canabinoid-1 receptor inverse agonist • obesity • appetite • satiety
30 kg/m2) and overweight (BMI 25–29.9 kg/m2) are increasing globally at an alarming rate and are associated with an increased risk of developing serious health problems.1 Management of obesity-related illnesses places a substantial burden on health care resources. In the United States alone, adult obesity-attributable medical expenditures were estimated to be $75 billion in 2003.2 An urgent medical need exists for long-term weight loss therapies that not only reduce caloric intake but also simultaneously promote energy expenditure via increases in metabolic rate. In this regard, use of cannabinoid-1 receptor (CB1R) inverse agonists to modulate food intake and energy expenditure represents an encouraging new therapeutic approach to treat obesity.3,4
|
Recently, a novel CB1R inverse agonist, taranabant (MK-0364), has been identified and is in clinical development as a potential new therapy for treating obesity.4 Taranabant produces a dose-dependent inhibition of food intake and weight gain, resulting in weight loss and decreased fat mass in preclinical models of obesity.15 In the clinical setting, taranabant reduces acute food intake over 24 hours and significantly increases energy expenditure between 2 and 5 hours postdose versus placebo in overweight/obese male volunteers.12,13
The present study in healthy men determined steady-state plasma pharmacokinetics of taranabant and its primary active metabolite M1 following once-daily administration for 14 days and assessed the potential effects on safety and tolerability, including mood state/alertness and cognitive/psychomotor function. This study also evaluated the pharmacodynamic effects of taranabant by using an appetite/satiety questionnaire.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
BMI 28 and had a mean body weight of 77.3 kg. Fifty subjects completed the study; 1 subject discontinued due to a clinical adverse experience (AE), 1 subject discontinued due to a laboratory AE, and 8 subjects discontinued due to early termination of one of the dosing panels due to an adverse event that was experienced by 1 subject in that panel. All subjects were in good general health according to routine medical history, physical examination, vital signs, and laboratory data; were nonsmokers (as assessed by history); and had creatinine clearances of at least 80 mL/min. Subjects were excluded if they had any relevant history of pulmonary, renal, hepatic, hematological, cardiovascular, gastrointestinal, psychiatric, or neurologic disease; diabetes; glaucoma; or any condition predisposing them to immunodeficiency.
The study was conducted at 2 study centers. Every subject gave written informed consent. The protocol was approved by the Ethical Review Committee of the University of Leuven (Leuven, Belgium) and the Commissie Voor Medische Ethiek (Antwerpen, Belgium) and was conducted in accordance with the guidelines established by the Declaration of Helsinki.
Study Design
This double-blind, randomized, placebo-controlled, 24-day study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of taranabant (5-25 mg once daily for 14 days) in healthy men. Panels included either 8 (n = 6 active, n = 2 placebo) or 12 subjects (n = 9 active, n = 3 placebo). On day 1, subjects were randomly administered a single dose of taranabant 5, 7.5, 10, or 25 mg or placebo followed by a washout on days 2 through 10. Beginning on day 11 (the first day of multiple-dose administration), each subject received taranabant (5, 7.5, 10, or 25 mg) or placebo once daily for 14 consecutive days (days 11-24; multiple-dose days 1-14).
Pharmacokinetic Assessments
Blood (4 mL) was drawn at predose and 1, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, 72, 96, 144, 192, and 240 hours postdose (days 1 and 24 only) for determination of plasma taranabant and its primary metabolite (M1) concentration. Plasma samples were then stored at –70°C until assayed.
Sequential timed collections of all voided urine for determination of taranabant and M1 concentration were obtained predose on day 1 and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 hours postdose on day 24. Urine was kept at 4°C during collection, and the volume was recorded to the nearest mL. After mixing urine with a bovine serum albumin solution, 3-mL aliquots were frozen at –70°C until assayed.
Plasma or urine taranabant samples were treated with acetonitrile to precipitate protein and centrifuged. Supernatants were then injected onto a Cohesive HTLC for online extraction on a Cyclone 0.5 x 50-mm, 60-µm column. The analytes were further separated by high-performance liquid chromatography (HPLC) on a Phenomenex Synergi Hydro-RP, 4-µm, 2 x 150-mm column with a gradient elution and a mobile phase of acetonitrile/0.1% formic acid solution. Detection of analytes was performed with a PE Sciex API 3000 mass spectrometer equipped with a turbo ion spray interface operated in positive ionization mode, monitoring precursor to product ion combinations of m/z 516 
353 for taranabant, m/z 532 232 for M1, and m/z 522 359 for internal standard in the multiple-reaction monitoring (MRM) mode. The internal standard for this assay was D6 taranabant. The limit of quantification (LOQ) for taranabant and M1 in plasma was 0.1 nM and 0.5 nM, respectively. The LOQ for taranabant and M1 in urine was 0.1 nM and 0.2 nM, respectively. The accuracy ranged from 90.0% to 110.0%, with less than 8.8% coefficient of variation (CV).
M1 samples from the 25-mg dose and 1 panel of the 10-mg dose (6 subjects) were analyzed using earlier analytical methods in which interferences from 2 other hydroxylated metabolites were observed. The pharmacokinetic parameters of M1 estimated for these subjects were excluded from the primary analysis. Only reliable M1 data—that is, the pharmacokinetic analysis for M1 following single-dose administration of taranabant up to 25 mg and following multiple doses of taranabant up to 10 mg—are included in this article.
Plasma concentrations and actual plasma sampling times were used to calculate the following taranabant and M1 pharmacokinetic parameters: the area under the plasma concentration-time curve (AUC0-24 h, AUC0-
), the maximum concentration observed in plasma (Cmax) and its time of occurrence (tmax), and the apparent terminal half-life (t1/2) for each subject following the first and last doses. Pharmacokinetic parameters were calculated using WinNonlin software Version 5.0.1 (Pharsight Corpora tion, Mountain View, California).
AUC0-last was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations up to the last measured concentration. AUC0- was determined as the sum of AUC0-last and the extrapolated area given by the quotient of the last measured concentration and 
. The Cmax and its tmax were obtained by inspection of the concentration-time data. The accumulation ratio for AUC0-24 h and Cmax was calculated as the ratio between day 14 and day 1 pharmacokinetic values. The accumulation half-life was estimated based on the observed accumulation ratio and dosing interval.
Taranabant and M1 concentrations in urine for the 25-mg dose were below the assay limit of quantification precluding determination of percent excretion in urine (fe) and renal clearance.
Pharmacodynamic Assessments
Subjects completed a validated visual analog scale (VAS) questionnaire16 to assess appetite and satiety at predose and 2, 4, 8, and 14 hours postdose on day 14 of multiple dosing. In addition, subjects completed the VAS evaluation form predose, pre-breakfast, pre-lunch, mid-afternoon, and at end of day on multiple-dose days 1, 4, 7, and 11. The questionnaire solicited responses to the following 5 questions: (1) How hungry do you feel now? (2) How much are you bothered or distracted by thoughts of food now? (3) How full do you feel now? (4) How easy do you find it to control your eating now? (5) How strong is your urge to eat now? Subjects answered these questions by placing a vertical line on a 100-mm horizontal line anchored at the ends with the polar descriptors not at all and extremely.
Hormone Assays
Blood for luteinizing hormone (LH), cortisol, and adrenocorticotropic hormone (ACTH) was obtained predose on days 1 and 24. Subjects fasted for at least 8 hours prior to obtaining the blood sample. Blood for LH was analyzed using an immunometric assay with electrochemoluminescence detection.
Blood for cortisol was analyzed using a radioimmunoassay (Immunotech; sensitivity 10 nM, CV 5.8%). After reviewing the data, it was decided not to assay the ACTH samples.
Safety
Physical examination, vital signs, 12-lead electrocardiograms (ECGs), routine safety laboratory measurements, urinalysis, and weight measurement were performed prestudy, at various time points postdosing, and at poststudy. Adverse experiences were monitored throughout the study and evaluated in terms of intensity (mild, moderate, or severe), duration, severity, outcome, and relationship to study drug.
Intraocular pressure (IOP) was measured using tonometry (Goldman Applanation) at predose on day 1 and at 24 hours postdose on day 24.
Subjects completed a Bond-Lader VAS questionnaire to assess mood/alertness at predose and 2, 8, and 24 hours postdose on days 1 and 24.17 Three factorial scores (alertness, contentedness, and calmness) were derived from 16 mood/alertness endpoints measured with the VAS. The 16 categories included alert/drowsy, calm/excited, strong/feeble, fuzzy/clear-headed, well coordinated/clumsy, lethargic/energetic, contented/discontented, troubled/tranquil, mentally slow/quick-witted, tense/relaxed, attentive/dreamy, incompetent/proficient, happy/sad, antagonistic/amicable, interested/bored, and withdrawn/gregarious. The mean changes from baseline were determined on days 1 and 24. The placebo groups for each panel were combined across panels.
The Digit Symbol Substitution Test (DSST) was given to subjects predose, 2 and 24 hours postdose (days 1 and 24), and poststudy to assess psychomotor performance and cognitive function. The DSST was adapted from the Wechsler Adult Intelligence Scale, Third Edition, digit symbol subtest,18 and is a simple and sensitive neuropsychological test to objectively evaluate cognitive function.
Statistical Analysis
Taranabant and M1 pharmacokinetic parameters (AUC0-24 h, AUC0-, Cmax, tmax, and apparent terminal t1/2) following single-dose administration or 14 days of taranabant multiple-dose administration were each analyzed using a mixed-effects analysis of variance (ANOVA) model with dose and day (day 1, multiple-dose day 14) as fixed factors and subject as a random factor.
Accumulation ratio of AUC0-24 h, Cmax, and C24 h was separately estimated by the geometric mean ratio (GMR) (point estimate and 90% confidence interval [CI]) of day 14/day 1 from a linear mixed model with dose and day (day 1, multiple-dose day 14) as fixed effects and subject as a random effect. To test the pharmacokinetic hypothesis that the taranabant plasma 
at steady state (multiple-dose day 14) was not altered to a significant extent compared with the single-dose 
(day 1), we applied a mixed-effects model to the log-transformed response (appropriate AUC) with day as a fixed effect and subject as a random effect. The GMRs and 90% CIs were derived by exponentiating the model-based log-scale means and confidence limits. The testing was performed following a step-up procedure in which the lowest dose of 5 mg was evaluated first. The hypothesis was to be declared to hold at a dose for which the 90% CI was contained within (0.70, 1.43).
The time to steady state was evaluated in an exploratory fashion via stepwise testing over successive ranges of time points using C24 h data from days 11 to 25 (multiple-dose days 1-15). Linear contrasts were constructed via a linear mixed model with day as a fixed effect and subject as a random effect.
Dose proportionality for AUC0-24 h on multiple-dose day 14 was assessed in an exploratory manner via a power-law model fitted on the log scale for AUC0-24 h and dose. An estimate of the slope associated with ln(dose) and the corresponding 95% CI was obtained from the model. A slope of 1 represents exact dose proportionality, whereas a large deviation from 1 indicates a lack of dose proportionality. A mean regression line of AUC0-24 h versus dose was plotted on the linear scale. Similar methods were applied to assess dose proportionality of Cmax on day 14, AUC0-, and Cmax on day 1.
All 60 subjects were included in the assessment of safety and tolerability. The effect of taranabant after multiple-dose administration on the change from baseline in VAS mood/alertness, VAS appetite/satiety, and DSST as compared with placebo was assessed using an ANOVA model for a parallel design.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
Taranabant plasma at steady state (multiple-dose day 14) was not significantly altered compared with the single-dose (day 1) at the 5-, 7.5-, and 10-mg doses (Table I), as evidenced by the fact that the 90% CIs for the GMRs were contained within the prespecified interval of (0.70, 1.43). However, for the 25-mg dose of taranabant, the at steady state was lower compared with the single-dose (GMR = 0.64), and the 90% CI (0.51, 0.80) was outside the prespecified interval.
|
The average accumulation ratios (day 14 vs day 1) for AUC0-24 h over the 14-day period were moderate for the 5-, 7.5-, and 10-mg doses (Table I), ranging from approximately 1.5- to 1.8-fold, with a corresponding accumulation half-life of approximately 15 to 21 hours. However, the 25-mg dose did not show any accumulation, as evidenced by a GMR for the AUC0-24 h ratio (day 14/day 1) of 1.04 (90% CI: 0.82, 1.31). Moderate accumulation in Cmax was also observed over the range of 5- to 10-mg doses (1.18- to 1.4-fold), but no accumulation was observed at the 25-mg dose. Steady state was reached by multiple-dose day 13 at all taranabant dose levels (Figure 3).
|
and Cmax on day 1 increased approximately dose proportionally over the range of doses studied.
M1 Pharmacokinetics
The plasma concentration profile for M1 generally paralleled that of the parent drug, although M1 circulates at plasma concentrations that are approximately 2- to 3-fold higher relative to plasma taranabant concentrations (Table II). The apparent terminal t1/2 for M1 was generally comparable to that of taranabant, suggesting formation rate-limited elimination. In addition, M1 accumulated similarly to taranabant and increased less than dose proportionally over dose for both AUC0-24 h and Cmax (Table II).
|
Pharmacodynamics
Although decreases in appetite were evident in the study on the basis of adverse experience reporting (Table III), multiple-dose administration of taranabant (5-25 mg daily over 14 days) resulted in no consistent change from baseline in the appetite/satiety VAS questionnaire measured at predose, pre-breakfast (2 hours postdose), pre-lunch, or mid-afternoon.
|
Safety
Taranabant was generally well tolerated up to 10 mg. Adverse events were generally of mild to moderate intensity, with higher doses being associated with greater frequency and severity of AEs. There were no significant changes in routine clinical safety parameters, including blood chemistry, hematology, urinalysis, ECGs, or vital signs. No serious clinical or laboratory AEs occurred during the study.
The 25-mg dose was discontinued after day 4 due to AEs. One subject experienced a transient episode of disorientation approximately 2 hours following dosing on day 2. This episode lasted for a few seconds and was accompanied by a sensation of lightheadedness, which lasted for approximately 1 hour. This subject was also noted to have emotional lability (depressed mood, feeling sad), which persisted for approximately 2 days. Two additional subjects reported emotional lability (inappropriate laughing and/or crying), sometimes with periods of unexpected sadness. All subjects fully recovered from these AEs, which were of mild to moderate intensity, with no persisting effects.
Fifty-six of 60 enrolled subjects reported a total of 315 clinical AEs (270 while on taranabant, 45 while on placebo), none of which was serious. Two hundred and seventeen of the 315 clinical AEs were considered possibly (137) or probably (80) drug related by the study investigators. There appeared to be dose-related increases in gastrointestinal and psychiatric-related AEs, and these were the most commonly reported drug-related AEs (Table III).
A total of 7 subjects receiving taranabant reported emotional lability (inappropriate laughing and/or crying, sometimes with periods of unexpected sadness): 2 subjects on taranabant 5 mg, 1 subject on taranabant 7.5 mg, 1 subject on taranabant 10 mg, and 3 subjects on taranabant 25 mg. One additional subject also reported 2 episodes of melancholy while on taranabant 25 mg. In addition to being more commonly reported following dosing of taranabant 25 mg, psychiatric-related AEs were also of greater intensity following administration of the top evaluated dose.
A total of 2 subjects discontinued during the study. One subject receiving taranabant 25 mg discontinued from the study after day 11 (multiple-dose day 1) due to a transient episode of disorientation accompanied by lightheadedness and emotional lability (depressed mood and feelings of sadness). The other subject was discontinued while receiving taranabant 5 mg for a laboratory AE on day 6 during the multiple-dose treatment period (elevated alanine aminotransferase [ALT] levels of 105 IU/L; upper limit of normal: 74 IU/L). ALT levels returned to within normal limits by the poststudy visit.
Taranabant across all dose levels produced no significant difference relative to placebo in the 3 factorial scores (alertness, contentedness, and calmness) of the mood/alertness VAS following 14-day multiple oral dose administration. Representative data (contentedness factorial score) are presented in Figure 4. Similarly, no significant differences relative to placebo occurred in cognitive function DSST endpoints for any of the studied taranabant doses following 14-day multiple oral dose administration. Representative data (total correct) are presented in Figure 5.
|
|
No statistically significant differences occurred in total cortisol or LH when compared with placebo at any of the dose groups, with the exception of an approximate 40% increase in LH that was observed predose on multiple-dose day 14 in the 25-mg dose group (data not shown).
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Preclinical weight loss efficacy studies in diet-induced obese (DIO) rats demonstrated a minimal effective taranabant dose of 0.3 mg/kg/day following chronic administration.15 In those studies, the mean plasma taranabant concentration at tmax was approximately 87 nM. With higher doses—up to 3.0 mg/kg/day—plasma taranabant levels also increased and produced correspondingly greater weight reduction efficacy in DIO rats. Based on pharmacokinetic data from a single-dose study in humans and assuming linear pharmacokinetics, it was estimated that taranabant doses in the range of 8 to 10 mg, administered once daily, would yield a maximum concentration (Cmax) of approximately 87 nM at steady state (day 14). Therefore, it was anticipated that a once-daily dose of 10 mg would approximate to the lower end of the clinically efficacious dose range in obese humans, with potentially still greater efficacy achievable at higher doses.
Plasma taranabant concentrations on days 1 and 14 reached peak concentrations after 1.0 to 3.0 hours, decreased rapidly from peak values with a half-life of approximately 2 to 3 hours, and then declined more slowly with an apparent terminal t1/2 ranging from 73.6 to 103.6 hours. Steady-state plasma levels of taranabant were generally achieved by day 13 of dosing at all dose levels. This finding is consistent with the apparent terminal half-life observed for taranabant. The average accumulation ratios for AUC0-24 h over the 14-day period ranged from approximately 1.5- to 1.8-fold for doses of 5, 7.5, and 10 mg, independent of dose, with a corresponding accumulation half-life of approximately 15 to 21 hours. There was no accumulation for the 25-mg dose. Following multiple-dose administration of taranabant, the taranabant plasma at steady state (multiple-dose day 14) was not altered to a significant extent compared with the single-dose (day 1) for the 5-, 7.5-, and 10-mg doses, suggesting that there are no time-dependent nonlinearities in pharmacokinetics in this dose range. In addition, after multiple-dose administration, AUC0-24 h and Cmax of taranabant increased dose proportionally over the dose range of 5 to 10 mg and increased somewhat less than dose proportionally at 25 mg. These results suggest potential autoinduction following once-daily administration of taranabant 25 mg. In contrast, the exposure and peak concentration after single doses were approximately dose proportional up to 200 mg of dose (manuscript submitted for publication). CYP3A4 is the primary enzyme involved in the metabolism of both taranabant and M1. The possible autoinduction observed at higher doses of taranabant after multiple-dose administration is consistent with in vitro data that both taranabant and M1 are inducers of CYP3A4 mRNA in cultures of human hepatocytes at concentrations of both 1 and 10 µM.
Plasma levels of the metabolite M1 were generally 2- to 3-fold higher than those of taranabant. The relative exposures of taranabant and M1 in human brain, however, are not clear, partially because the protein binding cannot be accurately estimated due to the high lipophilicity of these 2 compounds. In rats, both taranabant and M1 were brain penetrant, and the average taranabant concentration in rat brain was approximately 10-fold higher than that of M1, despite 2- to 5-fold higher plasma levels of the metabolite. Although neither taranabant nor M1 were substrates for human or mouse P-glycoprotein (P-gp), it is not clear whether M1 is a P-gp substrate in rat. M1 has approximately a 10-fold lower potency for binding to human CB1R relative to taranabant (IC50 = 2 nM for M1 and IC50 = 0.3 nM for taranabant). As an inverse agonist, M1 is approximately 2-fold less potent for inhibition of forskolin-stimulated adenylate cyclase activity in recombinant CB1R Chinese hamster ovary (CHO) cells (EC50 = 4 nM for M1 and 2 nM for taranabant). Taken together, it is not well understood how much M1 contributes to the overall activity of taranabant as well as the clinical significance of higher peripheral M1 exposures.
Previous in vitro and preclinical studies have shown that taranabant is extensively metabolized (primarily by CYP3A4) and is ultimately excreted in the feces. This is consistent with the present study, in which urinary concentrations of taranabant and its metabolite M1 were found to be below the assay limit of quantification at the highest 25-mg taranabant dose.
Multiple-dose administration of taranabant once daily for 14 days at doses up to 10 mg was generally well tolerated. Two subjects discontinued from the study as a result of AEs. Overall, however, no clinically significant, treatment-related effects of taranabant were apparent upon analysis of chemistry (including aspartate aminotransferase [AST] and ALT) and hematology laboratory parameters, serum cortisol, vital signs, or ECG parameters.
There appeared to be dose-related increases in gastrointestinal and psychiatric-related (eg, mental depression, emotional lability, melancholy) AEs, which were most commonly observed for taranabant doses of 10 and 25 mg and were of greater intensity following administration of taranabant 25 mg. Dose-related increases in these AEs may be consistent with the safety and tolerability profiles of other CB1R inverse agonists and may be mechanism mediated. Mood/alertness VAS questionnaire and DSST data in this study failed to reveal any obvious dose-related trends, although longer term studies in a much broader population are needed.
Natural cannabinoids and cannabimimetics reduce IOP,19,20 partly via interaction with CB1R receptors in the eye.19 The ocular hypotensive effect of cannabinoids can be attenuated with a CB1R inverse agonist,19 suggesting that clinical use of these agents may theoretically result in increases in IOP. In the present study, analysis of IOP data following multiple-dose administration of taranabant 10- and 25-mg doses suggests that the 25-mg dose may be associated with a small increase in IOP (
2.6 mm Hg), which is less than the normal diurnal variation in intraocular pressure (3-6 mm Hg) that has been reported in the literature.21 Taken together, the increase in IOP observed following taranabant 25 mg is not likely to be clinically significant.
Taranabant 25 mg also appears to be associated with modest increases (40%) in LH after multiple-dose administration. This finding is consistent with the assertion that CB1R are involved in the modulation of the hypothalamo-pituitary axis in animal models.22-25 The increases in IOP and LH are unlikely to be clinically meaningful in a clinical setting given that these changes were observed with the top evaluated dose in this study, which is likely to be substantially higher than the top therapeutic dose.
Although there were no apparent dose-related trends with regard to appetite or satiety, as assessed by a VAS questionnaire, it appears that taranabant multiple-dose administration may be associated with appetite suppression based on dose-related increases in AEs. These data are in keeping with the mechanism of action of CB1R inverse agonists and are consistent with the significant reduction in 24-hour food intake that was observed following taranabant single-dose administration.13
In summary, this is the first clinical study of the safety and tolerability, pharmacokinetics, and pharmacodynamics of taranabant multiple-dose administration in human subjects. Overall, taranabant was generally well tolerated up to 10 mg and exhibited linear pharmacokinetics up to 10 mg and multiple-dose pharmacokinetic characteristics consistent with a once-daily regimen.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Financial disclosure: This study was funded by Merck & Co, Inc.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. World Health Organization. Obesity fact sheet. Available at: www.who.int/mediacentre/factsheets/fs311/en/. Accessed May 7, 2007.
2. Finkelstein EA, Fiebelkorn IC, Wang G. State-level estimates of annual medical expenditures attributable to obesity. Obes Res. 2004;12: 18-24.[Web of Science][Medline] [Order article via Infotrieve]
3. Boyd ST, Fremming BA. Rimonabant: a selective CB1 antagonist. Ann Pharmacother. 2005;39: 684-690.
4. Lin LS, Lanza TJ Jr, Jewell JP, et al. Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem. 2006;49: 7584-7587.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Nicoll RA, Alger BE. The brain's own marijuana. Sci Am. 2004;291: 68-75.[Web of Science][Medline] [Order article via Infotrieve]
6. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3: 771-784.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141: 765-774.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Osei-Hyiaman D, Harvey-White J, Batkai S, Kunos G. The role of the endocannabinoid system in the control of energy homeostasis. Int J Obes (Lond). 2006;30(suppl 1): S33-S38.
9. Di Marzo V, De Petrocellis L, Bisogno T. Endocannabinoids part I: molecular basis of endocannabinoid formation, action and inactivation and development of selective inhibitors. Expert Opin Ther Targets. 2001;5: 241-265.[CrossRef][Medline] [Order article via Infotrieve]
10. Gardner EL. Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav. 2005;81: 263-284.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Freedland CS, Poston JS, Porrino LJ. Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding. Pharmacol Biochem Behav. 2000;67: 265-270.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Addy C, Heymsfield S, Cilissen C, et al. MK-0364, a novel cannabinoid-1 receptor inverse agonist, increases energy expenditure in overweight and moderately obese subjects [abstract 1828-P]. Presented at: American Diabetes Association, 67th Scientific Sessions; June 22-26, 2007; Chicago, Illinois.
13. Stevens C, Cilissen C, de Smet M, et al. MK-0364, a CB-1R inverse agonist, reduces acute food intake in overweight/obese male volunteers [abstract 1830-P]. Presented at: American Diabetes Association, 67th Scientific Sessions; June 22-26, 2007; Chicago, Illinois.
14. Henness S, Robinson DM, Lyseng-Williamson KA. Rimonabant. Drugs. 2006;66: 2109-2119.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Fong TM, Guan XM, Marsh DJ, et al. Anti-obesity efficacy of a novel cannabinoid-1 receptor inverse agonist MK-0364 in rodents. J Pharmacol Exp Ther. 2007;321: 1013-1022.
16. Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord. 2000;24: 38-48.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 1974;1974: 211-218.
18. Wechsler D. WAIS-R Manual. New York: Psychological Corporation; 1981.
19. Song ZH, Slowey CA. Involvement of cannabinoid receptors in the intraocular pressure-lowering effects of WIN55212-2. J Pharmacol Exp Ther. 2000;292: 136-139.
20. Colasanti BK. Ocular hypotensive effect of marihuana cannabinoids: correlate of central action or separate phenomenon? J Ocul Pharmacol. 1986;2: 295-304.[Medline] [Order article via Infotrieve]
21. Wilensky JT. Diurnal variations in intraocular pressure. Trans Am Ophthalmol Soc. 1991;89: 757-790.[Medline] [Order article via Infotrieve]
22. Barna I, Zelena D, Arszovszki AC, Ledent C. The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation: in vivo and in vitro studies in CB1 receptor knockout mice. Life Sci. 2004;75: 2959-2970.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
23. Weidenfeld J, Feldman S, Mechoulam R. Effect of the brain constituent anandamide, a cannabinoid receptor agonist, on the hypothalamo-pituitary-adrenal axis in the rat. Neuroendocrinology. 1994;59: 110-112.[Web of Science][Medline] [Order article via Infotrieve]
24. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology. 2004;145: 5431-5438.
25. Manzanares J, Corchero J, Fuentes JA. Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of delta(9)-tetrahydrocannabinol in rats. Brain Res. 1999;839: 173-179.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  J. I. Schwartz, S. Dunbar, J. Yuan, S. Li, D. L. Miller, K. Rosko, A. O. Johnson-Levonas, K. C. Lasseter, and J. A. Wagner Influence of Taranabant, an Orally Active, Highly Selective, Potent Cannabinoid-1 Receptor (CB1R) Inverse Agonist, on Ethinyl Estradiol and Norelgestromin Plasma Pharmacokinetics J. Clin. Pharmacol., January 1, 2009; 49(1): 72 - 79. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
