The exact neurochemical appetite suppressant effects of naltrexone/bupropion are not fully understood. Naltrexone is a mu-opioid antagonist and bupropion, a weak inhibitor of neuronal dopamine and norepinephrine reuptake. These components affect two principal areas of the brain, specifically the arcuate nucleus of the hypothalamus and the mesolimbic dopaminergic reward system.
In the arcuate nucleus of the hypothalamus, bupropion stimulates pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α-MSH), which in turn binds to and stimulates melanocortin 4 receptors (MC4-R). When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptors. Binding of β-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMC neurons leading to a decrease in the release of α-MSH. Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying the effects of bupropion on energy balance. Preclinical data suggests that naltrexone and bupropion may have greater than additive effects in this region to reduce food intake when administered together.
The results of a single dose relative bioavailability study in healthy subjects demonstrated that naltrexone/bupropion tablets, when dose adjusted, are bioequivalent based on AUC0-∞ mean ratio and 90% confidence intervals to naltrexone immediate release (IR) or bupropion prolonged release (PR) administered as single agents.
Following single oral administration of naltrexone/bupropion tablets to healthy subjects, peak concentrations of naltrexone and bupropion occurred approximately 2 and 3 hours post administration of naltrexone/bupropion, respectively. There were no differences in bioavailability, as measured by AUC, of naltrexone or bupropion when administered in combination compared to each administered alone. However, given the prolonged nature of the drug release for naltrexone/bupropion, Cmax for naltrexone was markedly reduced compared to the 50 mg naltrexone hydrochloride IR administered alone (about 2-fold difference after dose adjustment). The bupropion Cmax from naltrexone/bupropion (180 mg bupropion hydrochloride) was equivalent to the Cmax of bupropion PR (150 mg bupropion hydrochloride), indicating that the bupropion Cmax achieved with naltrexone/bupropion (360 mg bupropion hydrochloride/day) is comparable to that achieved with commercially available bupropion PR (300 mg bupropion hydrochloride/day) administered alone.
Naltrexone and bupropion are well absorbed from the gastrointestinal tract (>90% absorbed), however, naltrexone has a significant first pass effect thereby limiting systemic bioavailablity, with only 5-6% reaching the systemic circulation intact.
When naltrexone/bupropion was given with a high-fat meal the AUC and Cmax for naltrexone increased 2.1-fold and 3.7-fold and the AUC and Cmax for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect resulted in AUC and Cmax increases of 1.7- and 1.9-fold for naltrexone, and 1.1- and 1.3-fold for bupropion, respectively. Clinical experience included varying prandial conditions and supports the use of naltrexone/bupropion tablets with food.
The mean volume of distribution at steady state of oral naltrexone and bupropion given as naltrexgone/bupropion, Vss/F, was 5697 liters and 880 liters, respectively. Plasma protein binding is not extensive for naltrexone (21%) or bupropion (84%) indicating low potential for drug interactions by displacement.
Following single oral administration of naltrexone/bupropion tablets to healthy subjects, mean T½ elimination half-life was approximately 5 hours for naltrexone and 21 hours for bupropion.
The major metabolite of naltrexone is 6-beta-naltrexol. Though less potent than naltrexone, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone. Naltrexone and 6-beta-naltrexol are not metabolised by cytochrome P450 enzymes and in vitro studies indicate that there is no potential for inhibition or induction of important isozymes. Naltrexone is primarily metabolised to 6-beta-naltrexol by the dihydrodiol dehydrogenases (DD1, DD2 and DD4). Other major metabolic routes are the formation of the metabolites 2-hydroxy-3-O-methyl naltrexone and 2-hydroxy-3-O-methyl-6-beta-naltrexol, believed to be mediated by catechol-O-methyl transferases (COMT), and glucuronidation, thought to be mediated by UGT1A1 and UGT2B7.
Naltrexone and its metabolites are excreted primarily by the kidney (37 to 60% of the dose). The derived value for renal excretion of naltrexone after oral administration, adjusting for plasma protein binding, is 89 mL/min. The enzyme responsible for the main elimination pathway is not known. Faecal excretion is a minor elimination pathway.
Bupropion is extensively metabolised with three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. The metabolites have longer elimination half-lives than bupropion and accumulate to a greater extent. In vitro findings suggest that CYP2B6 is the principal isozyme involved in the formation of hydroxybupropion, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. In contrast, formation of threohydrobupropion has been reported in the literature to be mediated by 11-beta-hydroxysteroid dehydrogenase 1. The metabolic pathway responsible for the formation of erythrohydrobupropion is unknown.
Bupropion and its metabolites inhibit CYP2D6. Plasma protein binding of hydroxybupropion is similar to that of bupropion (84%) whereas the other two metabolites have approximately half the binding.
Following oral administration of 200 mg of 14C-bupropion hydrochloride in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral dose of bupropion excreted unchanged was 0.5%, a finding consistent with the extensive metabolism of bupropion.
Following twice daily administration of naltrexone/bupropion, naltrexone does not accumulate, while 6-beta-naltrexol accumulates over time. Based on its half-life, 6-beta-naltrexol is estimated to reach steady state concentrations in approximately 3 days. Metabolites of bupropion (and to a lesser extent unmetabolised bupropion) accumulate and reach steady state concentrations in approximately one week. No study has been performed comparing AUC or Cmax of naltrexone/bupropion prolonged-release tablets with bupropion PR or naltrexone IR administered as single agents in the multiple dose setting (i.e., under steady state conditions).
Pooled analysis of naltrexone/bupropion data revealed no meaningful gender or race-related differences in the pharmacokinetic parameters of bupropion or naltrexone. However, only Caucasian and Black subjects were investigated to a significant extent. No dosage adjustment is necessary based on gender or race.
The pharmacokinetics of naltrexone/bupropion have not been evaluated in the elderly population. Because naltrexone and bupropion metabolic products are excreted in the urine and elderly people are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Naltrexone/bupropion is not recommended in patients over 75 years of age.
Pooled analysis of naltrexone/bupropion data revealed no meaningful differences in the plasma concentrations of bupropion or naltrexone in smokers compared to nonsmokers. The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150 mg dose of bupropion hydrochloride, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.
A single-dose pharmacokinetic study has been conducted with naltrexone/bupropion in patients with hepatic impairment. The results from this study demonstrated that in patients with mild hepatic impairment (Child-Pugh scores of 5-6 [Class A]), there was a modest increase in naltrexone concentrations, but concentrations of bupropion and most other metabolites were mostly comparable and no more than doubled to those in patients with normal hepatic function. In patients with moderate (Child-Pugh scores of 7-9 [Class B]) and severe (Child-Pugh scores of 10 or higher [Class C]) hepatic impairment, increases in the maximum concentration of naltrexone of ~6- and ~30-fold were observed for the moderate and severe patients respectively, while increases in bupropion were ~2-fold for both groups. Increases of ~2- and ~4-fold for the area under the curve for bupropion were observed for patients with moderate and severe impairment respectively. There were no consistent changes in naltrexone or bupropion metabolites related to varying degrees of hepatic impairment. Naltrexone/bupropion is contraindicated in patients with severe hepatic impairment and is not recommended in patients with moderate hepatic impairment. In patients with mild hepatic impairment, the maximum recommended daily dose for naltrexone/bupropion should be reduced.
A single-dosepharmacokinetic study has been conducted for naltrexone/bupropion in subjects with mild, moderate, and severe renal impairment, compared with subjects with normal renal function. The results from this study demonstrated that the area under the curve for plasma naltrexone and metabolites and for plasma bupropion and metabolites was increased by less than two-fold in patients with moderate and severe renal impairment, and smaller increases were observed for patients with mild renal impairment. Based on these results, there are no dose adjustments recommended for patients with mild renal impairment. For patients with moderate or severe renal impairment, the maximum recommended daily dose for naltrexone/bupropion should be reduced. Naltrexone/bupropion is contraindicated in end-stage renal failure.
The effects of combined bupropion and naltrexone use have not been studied in animals.
Non-clinical data on individual components reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Any effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. However, there is some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymes have been found in humans with therapeutic and higher doses. Liver changes are seen in animal studies with bupropion but these reflect the action of a hepatic enzyme inducer. At recommended doses in humans, bupropion does not induce its own metabolism. This suggests that the hepatic findings in laboratory animals have only limited importance in the evaluation and risk assessment of bupropion.
Naltrexone (100 mg/kg/day, approximately 30 times the dose of naltrexone in naltrexone/bupropion on a mg/m² basis) caused a significant increase in pseudo-pregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.
Naltrexone has been shown to have an embryocidal effect in rats dosed with 100 mg/kg/day of naltrexone (30 times the naltrexone/bupropion dose) prior to and throughout gestation, and in rabbits treated with 60 mg/kg/day of naltrexone (36 times the naltrexone/bupropion dose) during the period of organogenesis.
A fertility study of bupropion in rats at doses up to 300 mg/kg/day, or 8 times the bupropion dose provided by naltrexone/bupropion revealed no evidence of impaired fertility.
Naltrexone was negative in the following in vitro genotoxicity studies: bacterial reverse mutation assay (Ames test), the heritable translocation assay, CHO cell sister chromatid exchange assay, and the mouse lymphoma gene mutation assay. Naltrexone was also negative in an in vivo mouse micronucleus assay. In contrast, naltrexone tested positive in the following assays: Drosophila recessive lethal frequency assay, non-specific DNA damage in repair tests with E. coli and WI-38 cells, and urinalysis for methylated histidine residues. The clinical relevance of these equivocal findings is unknown.
Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mammalian mutagen, and therefore is of no concern as a human genotoxic agent. Mouse and rat studies confirm the absence of carcinogenicity in these species.
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