Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: Other antidepressants, ATC code: N06 AX12.
Mechanism of action

Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines (noradrenaline and dopamine) with minimal effect on the re-uptake of indolamines (serotonin) and does not inhibit either monoamine oxidase.

The mechanism of action of bupropion as an antidepressant is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.

Clinical efficacy

The antidepressant activity of bupropion was studied in a clinical programme involving a total of 1155 WELLBUTRIN XR patients and 1868 WELLBUTRIN SR patients with Major Depressive Disorder (MDD). Seven of the studies examined the efficacy of WELLBUTRIN XR: 3 were conducted in the EU at doses up to 300 mg/day and 4 were conducted in the US over a flexible dose range of up to 450 mg/day. In addition, 9 studies in MDD with WELLBUTRIN SR are considered to be supportive based on the bioequivalence of WELLBUTRIN XR (once daily) to the SR (twice daily) tablet.

WELLBUTRIN XR demonstrated statistical superiority over placebo as measured by improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score in 1 of 2 identical studies utilising doses in the range 150-300 mg. Response and remission rates were also statistically significantly higher with WELLBUTRIN XR compared to placebo. In a third study in elderly patients, statistical superiority over placebo was not achieved on the primary 
parameter, mean change from baseline in MADRS (Last Observation Carried Forward endpoint) although statistically significant effects were seen on a secondary (Observed Case) analysis.

Significant benefit was shown on the primary endpoint in 2 of 4 US studies with WELLBUTRIN XR (300-450 mg). Of the 2 positive studies, one was a placebo controlled study in patients with MDD and one was an active controlled study in patients with MDD.

In a relapse prevention study, patients responding to 8 weeks of acute treatment with open-label WELLBUTRIN SR (300 mg/day) were randomised to either WELLBUTRIN SR or placebo for a further 44 weeks. WELLBUTRIN SR demonstrated a statistically significant superiority compared to placebo (P < 0.05) on the primary outcome measure. The incidence of maintenance of effect during the 44 week double blind follow-up period was 64% and 48% for WELLBUTRIN SR and placebo, respectively.

Clinical safety

The prospectively observed proportion of cardiac birth defects in pregnancies with prenatal exposure to bupropion in the first trimester in the international Pregnancy Registry was 9/675 (1.3%).

In a retrospective study there was no greater proportion of congenital malformations or cardiovascular malformations amongst more than a thousand first trimester exposures to bupropion compared with the use of other antidepressants.

In a retrospective analysis using data from the National Birth Defects Prevention Study, a statistically significant association was observed between the occurrence of a left outflow tract heart defect in the infant and self-reported maternal bupropion use in early pregnancy. No association was observed between maternal bupropion use and any other type of cardiac defect or with all categories of heart defects combined.

A further analysis of data from the Slone Epidemiology Center Birth Defects Study found no statistically significant increase of left outflow tract heart defects with maternal bupropion use.
However, a statistically significant association was observed for ventricular septal defects following the use of bupropion alone during the first trimester.

In a study in healthy volunteers, no clinically significant effect of modified release bupropion tablets (450 mg/day) compared with placebo was observed on QTcF interval after 14 days of dosing to steady state.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption
After oral administration of 300 mg bupropion hydrochloride once daily as the modified release tablet to healthy volunteers, maximum plasma concentrations (Cmax) of approximately 160 ng/ml are observed at approximately 5 hours. At steady state, the Cmax and AUC values of hydroxybupropion are approximately 3 and 14 times that of bupropion, respectively. The Cmax of threohydrobupropion at steady state is similar to that of bupropion and the AUC is approximately 5 times higher while the plasma concentrations of erythrohydrobupropion are comparable to those of bupropion. Peak plasma levels of hydroxybupropion are reached at 7 hours while those for threohydrobupropion and erythrohydrobupropion are reached at 8 hours.
The AUC and Cmax values of bupropion and its active metabolites hydroxybupropion and threohydrobupropion increase dose proportionally over a dose range of 50-200 mg following single doses and over a dose range of 300-450 mg/day following chronic dosing.


The absolute bioavailability of bupropion is not known; urinary excretion data, however, show that at least 87% of the dose of bupropion is absorbed.

The absorption of bupropion modified release tablets is not significantly influenced when taken concurrently with food.

Distribution
Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 L.

Bupropion, hydroxybupropion and threohydrobupropion bind moderately to plasma proteins (84%, 77% and 42%, respectively).

Bupropion and its active metabolites are excreted in human breast milk. Animal studies show that bupropion and its active metabolites pass the blood-brain barrier and the placenta. Positron Emision Tomography studies in healthy volunteers demonstrate that bupropion penetrates the CNS and binds to the striatal dopamine reuptake transporter (approximately 25% at 150 mg twice daily).

Biotransformation
Bupropion is extensively metabolised in humans. Three pharmacologically active metabolites have been identified in plasma: hydroxybupropion and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion. These may have clinical importance, as their plasma concentrations are as high or higher than those of bupropion. The active metabolites are further metabolised to inactive metabolites (some of which have not been fully characterised but may include conjugates) and excreted in the urine.

In vitro studies indicate that bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the CYP2B6, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. In contrast, formation of threohydrobupropion involves carbonyl reduction but does not involve cytochrome P450 isoenzymes (see section 4.5).
The inhibition potential of threohydrobupropion and erythrohydrobupropion towards cytochrome P450 has not been studied.

Bupropion and hydroxybupropion are both inhibitors of the CYP2D6 isoenzyme with Ki values of 21 and 13.3μM, respectively (see section 4.5).

Bupropion has been shown to induce its own metabolism in animals following sub-chronic administration. In humans, there is no evidence of enzyme induction of bupropion or hydroxybupropion in volunteers or patients receiving recommended doses of bupropion hydrochloride for 10 to 45 days.

Elimination
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. Less than 10% of this 14C dose was accounted for in the urine as active metabolites.

The mean apparent clearance following oral administration of bupropion hydrochloride is approximately 200 L/hr and the mean elimination half-life of bupropion is approximately 20 hours.


The elimination half-life of hydroxybupropion is approximately 20 hours. The elimination half- lives for threohydrobupropion and erythrohydrobupropion are longer (37 and 33 hours, respectively) and steady-state AUC values are 8 and 1.6 times higher than that of bupropion, respectively. Steady-state for bupropion and its metabolites is reached within 8 days.

The insoluble shell of the modified release tablet may remain intact during gastrointestinal transit and be eliminated in the faeces.

Special patient population:
Renal impairment
The elimination of bupropion and its active major metabolites may be reduced in patients with impaired renal function. Limited data in patients with end-stage renal failure or moderate to severely impaired renal function indicate that exposure to bupropion and/or its metabolites was increased (see section 4.4).

Hepatic impairment
The pharmacokinetics of bupropion and its active metabolites were not statistically significantly different in patients with mild to moderate cirrhosis when compared to healthy volunteers, although more variability was observed between individual patients (see section 4.4). For patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference approximately 70% and 3-fold, respectively) and more variable when compared to the values in healthy volunteers; the mean half-life was also longer (by approximately 40%). For hydroxybupropion, the mean Cmax was lower (by approximately 70%), the mean AUC tended to be higher (by approximately 30%), the median Tmax was later (by approximately 20 hrs), and the mean half-lives were longer (by approximately 4-fold) than in healthy volunteers. For threohydrobupropion and erythrohydrobupropion, the mean Cmax tended to be lower (by approximately 30%), the mean AUC tended to be higher (by approximately 50%), the median Tmax was later (by approximately 20 hrs), and the mean half-life was longer (by approximately 2-fold) than in healthy volunteers (see section 4.3).

Elderly
Pharmacokinetic studies in the elderly have shown variable results. A single dose study showed that the pharmacokinetics of bupropion and its metabolites in the elderly do not differ from those in the younger adults. Another pharmacokinetic study, single and multiple dose, has suggested that accumulation of bupropion and its metabolites may occur to a greater extent in the elderly.
Clinical experience has not identified differences in tolerability between older and younger patients, but greater sensitivity in older patients cannot be ruled out (see section 4.4).

In-vitro release of bupropion with alcohol
In-vitro tests showed that at high alcohol concentrations (up to 40%), bupropion is released more rapidly from the modified release formulation (up to 20% dissolved at 2 hours) (see section 4.5).