Celexa clinical pharmacology
Celexa Pharmacodynamics
The mechanism of action of Celexa HBr as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that Celexa is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with Celexa. Celexa is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by Celexa is primarily due to the (S)-enantiomer.
Celexa has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.
Celexa Pharmacokinetics
The single- and multiple-dose pharmacokinetics of Celexa are linear and dose-proportional in a dose range of 10-60 mg/day. Biotransformation of Celexa is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of Celexa in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. The tablet and oral solution dosage forms of Celexa HBr are bioequivalent.
Celexa Absorption and Distribution
Following a single oral dose (40 mg tablet) of Celexa, peak blood levels occur at about 4 hours. The absolute bioavailability of Celexa was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of Celexa is about 12 L/kg and the binding of Celexa (CT), demethylCelexa (DCT) and didemethylCelexa (DDCT) to human plasma proteins is about 80%.
Celexa Metabolism and Elimination
Following intravenous administrations of Celexa, the fraction of drug recovered in the urine as Celexa and DCT was about 10% and 5%, respectively. The systemic clearance of Celexa was 330 mL/min, with approximately 20% of that due to renal clearance.
Celexa is metabolized to demethylCelexa (DCT), didemethylCelexa (DDCT), Celexa-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged Celexa is the predominant compound in plasma. At steady state, the concentrations of Celexa’s metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that Celexa is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of Celexa.
In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of Celexa.
Celexa Population Subgroups
Age – Celexa pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, Celexa AUC and half-life were increased in the elderly subjects by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg is the recommended dose for most elderly patients.
Gender – In three pharmacokinetic studies (total N=32), Celexa AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum Celexa levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended.
Reduced hepatic function – Celexa oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg is the recommended dose for most hepatically impaired patients.
Reduced renal function – In patients with mild to moderate renal function impairment, oral clearance of Celexa was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of Celexa in patients with severely reduced renal function (creatinine clearance < 20 mL/min).
Celexa Drug-Drug Interactions
In vitro enzyme inhibition data did not reveal an inhibitory effect of Celexa on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Celexa would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited.
Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of Celexa, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of Celexa. However, coadministration of Celexa and the potent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of Celexa. Because Celexa is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease Celexa clearance. Celexa steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple-dose administration of Celexa, suggesting that coadministration, with Celexa, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on Celexa metabolism.
Celexa Clinical Efficacy Trials
The efficacy of Celexa as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18-66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed Celexa doses of 10, 20, 40, and 60 mg/day, showed that Celexa at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with Celexa showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving Celexa and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose.
In two long-term studies, depressed patients who had responded to Celexa during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study) were randomized to continuation of Celexa or to placebo. In both studies, patients receiving continued Celexa treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of Celexa.
Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Celexa Comparison of Clinical Trial Results
Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
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