12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

CONTRAVE has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood.

12.2 Pharmacodynamics

Combined, bupropion and naltrexone increased the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite. The combination of bupropion and naltrexone also reduced food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, an area associated with regulation of reward pathways.

Cardiac Electrophysiology

At the recommended dose, CONTRAVE does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

Naltrexone

Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak naltrexone concentration (Cmax) was 1.4 ng/mL, time to peak concentration (Tmax) was 2 hours, and extent of exposure (AUC0-inf) was 8.4 ng∙hr/mL.

Bupropion

Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak bupropion concentration (Cmax) was 168 ng/mL, time to peak concentration (Tmax) was three hours, and extent of exposure (AUC0-inf) was 1,607 ng∙hr/mL.

Food Effect on Absorption

When CONTRAVE was administered with a high-fat meal, the AUC and Cmax for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and Cmax for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and Cmax for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and Cmax for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, CONTRAVE should not be taken with high-fat meals because of the resulting significant increases in bupropion and naltrexone systemic exposure.

Distribution

Naltrexone

Naltrexone is 21% plasma protein bound. The mean apparent volume of distribution at steady state for naltrexone (Vss/F) is 5,697 liters.

Bupropion

Bupropion is 84% plasma protein bound. The mean apparent volume of distribution at steady state for bupropion (Vss/F) is 880 liters.

Metabolism and Excretion

Naltrexone

The major metabolite of naltrexone is 6-beta-naltrexol. The activity of naltrexone is believed to be the result of both the parent and the 6-beta-naltrexol metabolite. Though less potent, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone. Naltrexone and 6-beta-naltrexol are not metabolized by cytochrome P450 enzymes and in vitro studies indicate that there is no potential for inhibition or induction of important isozymes.

Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose). Urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose. Urinary excretion of unchanged and conjugated 6-beta-naltrexol accounts for 43% of an oral dose. The renal clearance for naltrexone ranges from 30 to 127 mL/min, suggesting that renal elimination is primarily by glomerular filtration. The renal clearance for 6-beta-naltrexol ranges from 230 to 369 mL/min suggesting an additional renal tubular secretory mechanism. Fecal excretion is a minor elimination pathway.

Following single oral administration of CONTRAVE tablets to healthy subjects, mean elimination half-life (T1/2) was approximately 5 hours for naltrexone. Following twice daily administration of CONTRAVE, naltrexone did not accumulate and its kinetics appeared linear. However, in comparison to naltrexone, 6-beta-naltrexol accumulates to a larger extent (accumulation ratio ~3).

Bupropion

Bupropion is extensively metabolized with three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. The metabolites have longer elimination half-lives than bupropion and accumulate to a greater extent. Following bupropion administration, more than 90% of the exposure is a result of metabolites. In vitro findings suggest that CYP2B6 is the principal isozyme involved in the formation of hydroxybupropion whereas cytochrome P450 isozymes are not involved in the formation of the other active metabolites. 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 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 single oral administration of CONTRAVE tablets to healthy subjects, mean elimination half-life (T½) was approximately 21 hours for bupropion. Following twice daily administration of CONTRAVE, metabolites of bupropion, and to a lesser extent unchanged bupropion, accumulate and reach steady-state concentrations in approximately one week.

Specific Populations

Gender

Pooled analysis of CONTRAVE data suggested no clinically meaningful differences in the pharmacokinetic parameters of bupropion or naltrexone based on gender.

Race

Pooled analysis of CONTRAVE data suggested no clinically meaningful differences in the pharmacokinetic parameters of bupropion or naltrexone based on race.

Elderly

The pharmacokinetics of CONTRAVE have not been evaluated in the geriatric population. The effects of age on the pharmacokinetics of naltrexone or bupropion and their metabolites have not been fully characterized. An exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations (8.5)].

Smokers

Pooled analysis of CONTRAVE data revealed no meaningful differences in the plasma concentrations of bupropion or naltrexone in smokers compared with 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, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Hepatic Impairment

A single dose pharmacokinetic study conducted for CONTRAVE, comparing patients with mild (n=8), moderate (n=8) and severe (n=7) hepatic impairment based on CHILD-PUGH classification system to subjects with normal hepatic function (n=13), showed that hepatic impairment had a significant effect on the PK parameters of the parent drugs naltrexone and bupropion. Systemic exposure to some metabolites was also increased in patients with impaired hepatic function [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Following a single dose of naltrexone/bupropion, AUCinf of naltrexone was approximately 2.8-, 6.1-, and 34-fold higher in patients with mild, moderate, and severe hepatic impairment, respectively. In patients with moderate and severe hepatic impairment, AUCinf of bupropion was approximately 2.0- and 3.6-fold higher, respectively, compared to subjects with normal hepatic function. There was no effect of mild hepatic impairment on bupropion exposure. Exposure to bupropion metabolite, threohydrobupropion, was increased by 1.9-, 3.4-, and 2.5-fold in patients with mild, moderate, and severe hepatic impairment, respectively [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Renal Impairment

A single-dose pharmacokinetic study conducted for CONTRAVE, comparing patients with mild (n=8), moderate (n=8) and severe (n=7) renal impairment to subjects with normal renal function (n=13), showed that renal impairment had no significant effect on the PK parameters of the parent drugs naltrexone and bupropion. However, systemic exposure (AUCinf) of some metabolites was increased in patients with impairment of renal function [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Following a single-dose of 16 mg naltrexone /180 mg bupropion, AUCinf of 6-beta-naltrexol was approximately1.5-, 1.7-, and 2.2-fold higher in patients with mild, moderate, and severe renal impairment, respectively. In patients with mild, moderate, and severe renal impairment, AUC of bupropion metabolites threohydrobupropion and erythrohydrobupropion increased approximately 1.3-, 1.9-, and 1.7-fold and 1.2-, 1.8-, and 1.5-fold, respectively. No studies have been conducted for CONTRAVE in patients with end stage renal disease.

The following information is available for individual components.

In a study of seven patients with end-stage renal disease requiring dialysis, peak plasma concentrations of naltrexone were elevated at least 6-fold compared to healthy subjects. An inter-trial comparison between normal subjects and patients with end-stage renal failure demonstrated that the bupropion Cmax and AUC values were comparable in the two groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure.

Drug Interactions

In Vitro Assessment of Drug Interactions

At therapeutically relevant concentrations, naltrexone and 6-beta-naltrexol are not major inhibitors of CYP isoforms CYP1A2, CYP2B6, CYP2C8, CYP2E1, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Both naltrexone and 6-beta-naltrexol are not major inducers of CYP isoforms CYP1A2, CYP2B6, or CYP3A4.

Bupropion and its metabolites (hydroxybupropion, erythrohydrobupropion, threohydrobupropion) are inhibitors of CYP2D6.

In vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

Bupropion (IC50 9.3 mcM) and its metabolites, hydroxybupropion (IC50 82 mcM) and threohydrobupropion and erythrohydrobupropion (1:1 mixture; IC50 7.8 mcM), inhibited the renal organic transporter OCT2 to a clinically relevant level.

Effects of Naltrexone/Bupropion on the Pharmacokinetics of Other Drugs

Drug interaction between CONTRAVE and CYP2D6 substrates (metoprolol) or other drugs (atorvastatin, glyburide, lisinopril, nifedipine, valsartan) has been evaluated. In addition, drug interaction between bupropion, a component of CONTRAVE, and CYP2D6 substrates (desipramine) or other drugs (citalopram, lamotrigine) has also been evaluated.

Table 4. Effect of Naltrexone/Bupropion Coadministration on Systemic Exposure of Other Drugs
Naltrexone/Bupropion Dosage	Coadministered Drug
Naltrexone/Bupropion Dosage	Name and Dose Regimens	Change in Systemic Exposure
Initiate the following drugs at the lower end of the dose range during concomitant use with CONTRAVE [see Drug Interactions 7]:
Bupropion 150 mg twice daily for 10 days	Desipramine 50 mg single dose	↑5-fold AUC, ↑2-fold Cmax
Bupropion 300 mg (as XL) once daily for 14 days	Citalopram 40 mg once daily for 14 days	↑40% AUC, ↑30% Cmax
Naltrexone/Bupropion 16 mg/180 mg twice daily for 7 days	Metoprolol 50 mg single dose	↑4-fold AUC, ↑2-fold Cmax
No dose adjustment needed for the following drugs during concomitant use with CONTRAVE:
Naltrexone/Bupropion 16 mg/180 mg single dose	Atorvastatin 80 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Glyburide 6 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Lisinopril 40 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg twice daily	Metformin 850 mg single dose	↑23% AUC; No effect on Cmax
Naltrexone/Bupropion 16 mg/180 mg single dose	Nifedipine 90 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Valsartan 320 mg single dose	No Effect
Bupropion 150 mg twice daily for 12 days	Lamotrigine 100 mg single dose	No Effect

Digoxin: Literature data showed that digoxin exposure was decreased when a single oral dose of 0.5 mg digoxin was administered 24 hours after a single oral dose of extended-release 150 mg bupropion in healthy volunteers.

Effects of Other Drugs on the Pharmacokinetics of Naltrexone/Bupropion

Drug interactions between CYP2B6 inhibitors (ticlopidine, clopidogrel, prasugrel), CYP2B6 inducers (ritonavir, lopinavir) and bupropion (one of the CONTRAVE components), or between other drugs (atorvastatin, glyburide, metoprolol, lisinopril, nifedipine, valsartan) and CONTRAVE have been evaluated. While not systematically studied, carbamazepine, phenobarbital, or phenytoin may induce the metabolism of bupropion.

Table 5. Effect of Coadministered Drugs on Systemic Exposure of Naltrexone/Bupropion
Name and Dose Regimens	Coadministered Drug
Name and Dose Regimens	CONTRAVE Components	Change in Systemic Exposure
* Results were confounded by the food-effect due to oral glucose coadministered with the treatment.
Do not exceed one tablet twice daily dose of CONTRAVE with the following drugs:
Ticlopidine 250 mg twice daily for 4 days	Bupropion Hydroxybupropion	↑85% AUC, ↑38% Cmax ↓84% AUC, ↓78% Cmax
Clopidogrel 75 mg once daily for 4 days	Bupropion Hydroxybupropion	↑60% AUC, ↑40% Cmax ↓52% AUC, ↓50% Cmax
No dose adjustment needed for CONTRAVE with the following drugs:
Atorvastatin 80 mg single dose	Naltrexone 6-beta naltrexol Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	No Effect No Effect No Effect No Effect No Effect No Effect
Lisinopril 40 mg single dose	Naltrexone 6-beta naltrexol Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	No Effect No Effect No Effect No Effect No Effect No Effect
Valsartan 320 mg single dose	Naltrexone 6-beta naltrexol Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	No Effect No Effect No Effect ↓14% AUC, No Effect on Cmax No Effect No Effect
Cimetidine 800 mg single dose	Bupropion Hydroxybupropion Threo/Erythrohydrobupropion	No Effect No Effect ↑16% AUC, ↑32% Cmax
Citalopram 40 mg once daily for 14 days	Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	No Effect No Effect No Effect No Effect
Metoprolol 50 mg single dose	Naltrexone 6-beta naltrexol Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	↓25% AUC, ↓29% Cmax No Effect No Effect No Effect No Effect No Effect
Metformin 850 mg single dose	Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion Naltrexone 6-beta naltrexol	No Effect No Effect No Effect No Effect No Effect No Effect
Nifedipine 90 mg single dose	Naltrexone 6-beta naltrexol Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	↑24% AUC, ↑58% Cmax No Effect No Effect on AUC, ↑22% Cmax No Effect No Effect No Effect
Prasugrel 10 mg once daily for 6 days	Bupropion Hydroxybupropion	↑18% AUC, ↑14% Cmax ↓24%AUC, ↓32% Cmax
Use CONTRAVE with caution with the following drugs:
Glyburide 6 mg single dose*	Naltrexone 6-beta naltrexol Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	↑2-fold AUC, ↑2-fold Cmax No Effect ↑36% AUC, ↑18% Cmax ↑22% AUC, ↑21% Cmax No Effect on AUC, ↑15% Cmax No Effect
Avoid concomitant use of CONTRAVE with following drugs:
Ritonavir 100 mg twice daily for 17 days	Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	↓22% AUC, ↓21 % Cmax ↓23% AUC, No Effect on Cmax ↓38% AUC, ↓39 % Cmax ↓48% AUC, ↓28 % Cmax
600 mg twice daily for 8 days	Bupropion Hydroxybupropion Threohydrobupropion Erythrohydrobupropion	↓66% AUC, ↓62% Cmax ↓78% AUC, ↓42 % Cmax ↓50% AUC, ↓58% Cmax ↓68% AUC, ↓48 % Cmax
Lopinavir/Ritonavir 400 mg/100 mg twice daily for 14 days	Bupropion Hydroxybupropion	↓57% AUC, ↓57% Cmax ↓50% AUC, ↓31% Cmax
Efavirenz 600 mg once daily for 2 weeks	Bupropion Hydroxybupropion	↓55% AUC, ↓34% Cmax No Effect on AUC, ↑50% Cmax