Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, drugs used in addictive disorders, ATC code: N07BC51.

Mechanism of action
Buprenorphine is an opioid partial agonist/antagonist which binds to the  and  (kappa) opioid receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the -opioid receptors which, over a prolonged period, might minimise the need of addicted patients for drugs.

Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent persons.

Naloxone is an antagonist at -opioid receptors. When administered orally or sublingually in usual doses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacological effect because of its almost complete first pass metabolism. However, when administered intravenously to opioid-dependent persons, the presence of naloxone in Suboxone produces marked opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.

Clinical efficacy and safety
Efficacy and safety data for buprenorphine/naloxone are primarily derived from a one-year clinical trial, comprising a 4-week randomised double blind comparison of buprenorphine/naloxone, buprenorphine and placebo followed by a 48 week safety study of buprenorphine/naloxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either buprenorphine/naloxone 16 mg per day, 16 mg buprenorphine per day or placebo. For subjects randomized to either active treatment, dosing began with 8 mg of buprenorphine on Day 1, followed by 16 mg (two 8 mg) of buprenorphine on Day 2. On Day 3, those randomized to receive buprenorphine/naloxone were switched to the combination tablet. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. The primary study comparison was to assess the efficacy of buprenorphine and buprenorphine/naloxone individually against placebo.
The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine/naloxone versus placebo (p < 0.0001) and buprenorphine versus placebo (p < 0.0001).

In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution versus a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg/day of buprenorphine/naloxone), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually. Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Buprenorphine
Absorption:
Buprenorphine, when taken orally, undergoes first-pass metabolism with N-dealkylation and glucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oral route is therefore inappropriate.

Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with increasing sublingual dose of buprenorphine/naloxone. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 4-16 mg), although the increase was less than dose-proportional.

Table 2: Buprenorphine Mean Pharmacokinetic Parameters

Pharmacokinetic Parameter         Suboxone 4 mg        Suboxone 8 mg           Suboxone 16 mg 
Cmax ng/ml                            1.84 (39)             3.0 (51)               5.95 (38) 
AUC0-48                              12.52 (35)           20.22 (43)              34.89 (33) hour ng/ml

Table 3. Changes in pharmacokinetic parameters for Suboxone film administered sublingually or buccally in comparison to Suboxone sublingual tablet


Dosage        PK          Increase in Buprenorphine             PK          Increase in Naloxone Parameter   Film         Film       Film          Parameter   Film         Film        Film Sublingual Buccal       Buccal                    Sublingual Buccal        Buccal Compared Compared Compared                        Compared Compared        Compared to Tablet    to Tablet  to Film                   to Tablet    to Tablet   to Film Sublingual Sublingual Sublingual                  Sublingual Sublingual    Sublingual 1×            Cmax        22 %         25 %       -             Cmax        -            -           -  2 mg/0.5 mg   AUC0-last   -            19 %       -             AUC0-last   -            -           -
2×            Cmax        -            21 %       21 %          Cmax        -            17 %        21 %
2 mg/0.5 mg   AUC0-last   -            23 %       16 %          AUC0-last   -            22 %        24 %
1×            Cmax        28 %         34 %       -             Cmax        41 %         54 %        - 8 mg/2 mg     AUC0-last   20 %         25 %       -             AUC0-last   30 %         43 %        - 1×            Cmax        37 %         47 %       -             Cmax        57 %         72 %        9% 12 mg/3 mg    AUC0-last   21 %         29 %       -             AUC0-last   45 %         57 %        - 1×            Cmax        -            27 %       13 %          Cmax        17 %         38 %        19 % 8 mg/2 mg     AUC0-last   -            23 %       -             AUC0-last   -            30 %        19 % plus
2×
2 mg/0.5 mg
Note 1. ‘– ‘represents no change when the 90 % confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80 % to 125 % limit.
Note 2. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to the 2 mg/0.5 mg strength film and has the same size as the 2 × 2 mg/0.5 mg film strength.

Distribution
The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours).

Buprenorphine is highly lipophilic, which leads to rapid penetration of the blood-brain barrier.
Buprenorphine is approximately 96 % protein bound, primarily to alpha and beta globulin.

Biotransformation
Buprenorphine is primarily metabolised through N-dealkylation by liver microsomal CYP3A4. The parent molecule and the primary dealkylated metabolite, norbuprenorphine, undergo subsequent glucuronidation. Norbuprenorphine binds to opioid receptors in vitro; however, it is not known whether norbuprenorphine contributes to the overall effect of buprenorphine/naloxone.

Elimination
Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of 32 hours.
Buprenorphine is excreted in the faeces (~70 %) by biliary excretion of the glucuroconjugated metabolites, the rest (~30 %) being excreted in the urine.

Linearity/non-linearity
Buprenorphine Cmax and AUC increased in a linear fashion with the increasing dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional.

Naloxone

Absorption and distribution
Following sublingual administration of buprenorphine/naloxone, plasma naloxone concentrations are low and decline rapidly. Naloxone mean peak plasma concentrations were too low to assess dose- proportionality.

Naloxone has not been found to affect the pharmacokinetics of buprenorphine, and both buprenorphine sublingual tablets and buprenorphine/naloxone sublingual film deliver similar plasma concentrations of buprenorphine.

Distribution
Naloxone is approximately 45 % protein bound, primarily to albumin.

Biotransformation
Naloxone is metabolized in the liver, primarily by glucuronide conjugation, and excreted in the urine.
Naloxone undergoes direct glucuronidation to naloxone 3-glucuronide, as well as N-dealkylation and reduction of the 6-oxo group.

Elimination
Naloxone is excreted in the urine, with a mean half-life of elimination from plasma ranging from 0.9 to 9 hours.

Special populations

Elderly
No pharmacokinetic data in elderly patients are available.
Renal impairment
Renal elimination plays a relatively small role (~30 %) in the overall clearance of buprenorphine/naloxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment (see section 4.3).

Hepatic impairment
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study.

Table 4 summarizes the results from a clinical trial in which the exposure of buprenorphine and naloxone was determined after administering a buprenorphine/naloxone 2.0/0.5 mg sublingual tablet in healthy subjects, and in subjects with varied degrees of hepatic impairment.


Table 4. Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine and naloxone following Suboxone administration (change relative to healthy subjects) 
Moderate Hepatic             Severe Hepatic
Mild Hepatic Impairment
Impairment                 Impairment
PK Parameter           (Child-Pugh Class A)
(Child-Pugh Class B)       (Child-Pugh Class C)
(n=9)
(n=8)                      (n=8)
Buprenorphine

Cmax                      1.2-fold increase              1.1-fold Increase         1.7-fold increase 
AUClast                   Similar to control             1.6-fold increase         2.8-fold increase 

Naloxone

Cmax                      Similar to control             2.7-fold increase        11.3-fold increase 
AUClast                   0.2-fold decrease              3.2-fold increase        14.0-fold increase 

Overall, buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function, while naloxone plasma exposure increased 14-fold with severely impaired hepatic function.