Campral (Acamprosate Calcium) - Description and Clinical Pharmacology

DESCRIPTION

CAMPRAL ^®(acamprosate calcium) is supplied in an enteric-coated tablet for oral administration. Acamprosate calcium is a synthetic compound with a chemical structure similar to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino acid neurotransmitter γ-aminobutyric acid and the amino acid neuromodulator taurine. Its chemical name is calcium acetylaminopropane sulfonate. Its chemical formula is C₁₀H₂₀N₂O₈S₂Ca and molecular weight is 400.48. Its structural formula is:

Acamprosate calcium is a white, odorless or nearly odorless powder. It is freely soluble in water, and practically insoluble in absolute ethanol and dichloromethane.

Each CAMPRAL ^® tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in CAMPRAL ^® tablets include: crospovidone, microcrystalline cellulose, magnesium silicate, sodium starch glycolate, colloidal anhydrous silica, magnesium stearate, talc, propylene glycol and Eudragit^® L 30 D or equivalent. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product.

CLINICAL PHARMACOLOGY

Pharmacodynamics

The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. In vitro and in vivo studies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance.

Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in alcohol-dependent animals in a dose-dependent manner and that this effect appears to be specific to alcohol and the mechanisms of alcohol dependence.

Acamprosate calcium has negligible observable central nervous system (CNS) activity in animals outside of its effects on alcohol dependence, exhibiting no anticonvulsant, antidepressant, or anxiolytic activity.

The administration of acamprosate calcium is not associated with the development of tolerance or dependence in animal studies.

CAMPRAL ^® is not known to cause alcohol aversion and does not cause a disulfiram-like reaction as a result of ethanol ingestion.

Pharmacokinetics

Absorption

The absolute bioavailability of CAMPRAL ^® after oral administration is about 11%. Steady-state plasma concentrations of acamprosate are reached within 5 days of dosing. Steady-state peak plasma concentrations after CAMPRAL ^® doses of 2 x 333 mg tablets three times daily average 350 ng/mL and occur at 3-8 hours post-dose. Coadministration of CAMPRAL ^® with food decreases bioavailability as measured by C_max and AUC, by approximately 42% and 23%, respectively. The food effect on absorption is not clinically significant and no adjustment of dose is necessary.

Distribution

The volume of distribution for acamprosate following intravenous administration is estimated to be 72-109 liters (approximately 1 L/kg). Plasma protein binding of acamprosate is negligible.

Metabolism

Acamprosate does not undergo metabolism.

Elimination

After oral dosing of 2 x 333 mg of CAMPRAL ^®, the terminal half-life ranges from approximately 20 - 33 hours. Following oral administration of CAMPRAL ^®, the major route of excretion is via the kidneys as acamprosate.

Special Populations

Gender : CAMPRAL ^® does not exhibit any significant pharmacokinetic differences between male and female subjects.

Age: The pharmacokinetics of CAMPRAL ^® have not been evaluated in a geriatric population. However, since renal function diminishes in elderly patients and acamprosate is excreted unchanged in urine, acamprosate plasma concentrations are likely to be higher in the elderly population compared to younger adults.

Pediatrics: The pharmacokinetics of CAMPRAL ^® have not been evaluated in a pediatric population.

Renal Impairment: Peak plasma concentrations after administration of a single dose of 2 x 333 mg CAMPRAL ^® tablets to patients with moderate or severe renal impairment were about 2-fold and 4-fold higher, respectively, compared to healthy subjects. Similarly, elimination half-life was about 1.8-fold and 2.6-fold longer, respectively, compared to healthy subjects. There is a linear relationship between creatinine clearance values and total apparent plasma clearance, renal clearance and plasma half-life of acamprosate. A dose of 1 x 333 mg CAMPRAL ^®, three times daily, is recommended in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min, see also PRECAUTIONS).

Patients with severe renal impairment (creatinine clearance ≤30 mL/min) should not be given CAMPRAL ^® (see also CONTRAINDICATIONS).

Hepatic Impairment: Acamprosate is not metabolized by the liver and the pharmacokinetics of CAMPRAL ^® are not altered in patients with mild to moderate hepatic impairment (groups A and B of the Child-Pugh classification). No adjustment of dosage is recommended in such patients.

Alcohol-dependent subjects: A cross-study comparison of CAMPRAL ^® at doses of 2 x 333 mg three times daily indicated similar pharmacokinetics between alcohol-dependent subjects and healthy subjects.

Drug-Drug Interactions

Acamprosate had no inducing potential on the cytochrome CYP1A2 and 3A4 systems, and in vitro inhibition studies suggest that acamprosate does not inhibit in vivo metabolism mediated by cytochrome CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. The pharmacokinetics of CAMPRAL ^® were unaffected when co-administered with alcohol, disulfiram or diazepam. Similarly, the pharmacokinetics of ethanol, diazepam and nordiazepam, imipramine and desipramine, naltrexone and 6-beta naltrexol were unaffected following co-administration with CAMPRAL ^®. However, co-administration of CAMPRAL ^® with naltrexone led to a 33% increase in the C_max and a 25% increase in the AUC of acamprosate. No adjustment of dosage is recommended in such patients.

CLINICAL STUDIES

The efficacy of CAMPRAL ^® in the maintenance of abstinence was supported by three clinical studies involving a total of 998 patients who were administered at least one dose of CAMPRAL ^® or placebo as an adjunct to psychosocial therapy. Each study was a double-blind, placebo-controlled trial in alcohol-dependent patients who had undergone inpatient detoxification and were abstinent from alcohol on the day of randomization. Study durations ranged from 90 days to 360 days. CAMPRAL ^® proved superior to placebo in maintaining abstinence, as indicated by a greater percentage of subjects being assessed as continuously abstinent throughout treatment.

In a fourth study, the efficacy of CAMPRAL ^® was evaluated in alcoholics, including patients with a history of polysubstance abuse and patients who had not undergone detoxification and were not required to be abstinent at baseline. This study failed to demonstrate superiority of CAMPRAL ^® over placebo.