Review
Pharmacokinetics of the combination tablet of buprenorphine and naloxone

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Abstract

The sublingual combination tablet formulation of buprenorphine and naloxone at a fixed dose ratio of 4:1 has been shown to be as effective as the tablet formulation containing only buprenorphine in treating opiate addiction. The addition of naloxone does not affect the efficacy of buprenorphine for two reasons: (1) naloxone is poorly absorbed sublingually relative to buprenorphine and (2) the half-life for buprenorphine is much longer than for naloxone (32 vs. 1 h for naloxone). The sublingual absorption of buprenorphine is rapid and the peak plasma concentration occurs 1 h after dosing. The plasma levels for naloxone are much lower and decline much more rapidly than those for buprenorphine. Increasing dose results in increasing plasma levels of buprenorphine, although this increase is not directly dose-proportional. There is a large inter-subject variability in plasma buprenorphine levels. Due to the large individual variability in opiate dependence level and the large variability in the pharmacokinetics (PK) of buprenorphine, the effective dose or effective plasma concentration is also quite variable. Doses must be titrated to a clinically effective level for individual patients.

Introduction

A combination tablet containing buprenorphine and naloxone at a fixed dose ratio of 4:1 (2 mg buprenorphine:0.5 mg naloxone and 8 mg buprenorphine:2 mg naloxone) has been approved by the Food and Drug Administration (FDA) for treating opiate dependence. The daily recommended dose of the combination tablet of buprenorphine and naloxone will probably range from 4:1 to 24:6 mg depending on the individual patient's dependence level (Johnson et al., this volume). Buprenorphine, a long acting mu-opiate partial agonist (Jasinski et al., 1978) has been shown to be effective for treating opiate-dependence (Johnson et al., 1992, Fudala and Johnson, 1995, Bickel and Amass, 1995, Ling et al., 1998). Naloxone is a short-acting opiate antagonist and can precipitate a moderate to severe withdrawal syndrome in opiate-dependent individuals (Jasinski et al., 1978, O'Brien et al., 1978). The addition of naloxone to the buprenorphine tablet is intended to reduce the abuse potential of buprenorphine. When buprenorphine and naloxone at a 4:1 ratio were given intravenously to opiate-dependent individuals, the combination dose precipitated opiate-withdrawal signs and symptoms (Fudala et al., 1998, Mendelson et al., 1999). Taken sublingually, the addition of naloxone does not affect the efficacy or pharmacological effects of buprenorphine (Walsh and Eissenberg, 2003, Harris et al., 2000) because of the differential in both sublingual absorption (40% for buprenorphine vs. 10% for naloxone for the solution formulation) (Harris et al., 2000) and duration of action (1 day for buprenorphine vs. 1 h for naloxone) (Jasinski et al., 1978, Berkowitz, 1976). Because of its anticipated limited abuse potential, this combination formulation is expected to be useful in a broad treatment setting that includes office-based practice (Bridge et al., 2003).

This report summarizes the pharmacokinetics (PK) and metabolism data for buprenorphine and naloxone focusing specifically on the combination tablet. Data for a buprenorphine solution formulation (typically containing 30% ethanol) will also be presented since it was the formulation used in earlier clinical trials, which provided the basic efficacy data for the buprenorphine alone product. These data in turn provided a significant portion of the data supporting the safety and efficacy of the combination product.

Section snippets

Analytical methods

Immunoassay was the method used in most PK studies for buprenorphine in the 1980s (Moore, 1995). The antisera used in these assays typically cross-reacted with one of buprenorphine's primary metabolites, either norbuprenorphine or the glucuronide conjugate of buprenorphine, the extent of which depended on the hapten used to generate the antisera. However, most of the PK studies conducted at the doses relevant for treating opiate addiction were performed in the 1990s. By this time, more specific

Absorption and distribution

Buprenorphine is a very lipophilic compound, which readily permeates the gastrointestinal and oral mucosal membrane. However, the oral bioavailability of buprenorphine is very poor (Walter and Inturrisi, 1995) because of a significant first-pass effect. Sublingual administration provides a way to avoid first pass metabolism, but low availability may still occur if part of the dose is swallowed rather than kept under the tongue. The sublingual uptake of buprenorphine is rapid—generally complete

Naloxone

Naloxone is more hydrophilic than buprenorphine. The sublingual absorption of naloxone was significantly lower than that of buprenorphine when determined by either measurement of the unabsorbed drug in the oral rinse (Weinberg et al., 1988) or by classic bioavailability studies (Harris et al., 2000). Naloxone is also rapidly distributed to the brain and has a high brain to plasma ratio (Berkowitz, 1976).

Naloxone is rapidly metabolized by glucuronidation, N-dealkylation and reduction of the

Pharmacokinetics for the intravenous route of administration

In early studies in surgical patients, plasma buprenorphine levels, measured by an immunoassay method, followed a multi-exponential decline after the intravenous administration of 0.3 and 0.6 mg doses of buprenorphine. The half-life was variously reported to be 2–5 h and appeared to depend on when the last plasma sample was taken (Bullingham et al., 1980, Bullingham et al., 1982, Watson et al., 1982).

A summary of the PK parameters for buprenorphine from recent studies, using more specific assay

Bioavailability—solution

When administered sublingually in a 30% alcohol solution, the mucosal absorption for buprenorphine was rapid. Absolute bioavailability of approximately 30% was reported for the 2 mg solution dose held under the tongue for either 3 or 5 min (Mendelson et al., 1997). Bioavailability of 51% was reported in a separate study when a 4 mg solution dose was compared with a 1.2 mg intravenous dose (Kuhlman et al., 1996). There was wide variation between subjects in the amount of buprenorphine absorbed

Factors that affect the pharmacokinetics of buprenorphine

A population PK analysis was conducted for the data collected in the above multicenter clinical trial using NONlinear Mixed Effects Modeling (NONMEN) (Boeckmann et al., 1992). The data suggest a decrease in buprenorphine clearance with increase in age, aspartate transaminase (AST) or alanine aminotransferase (ALT) (Holford, 2000). Buprenorphine clearance may decrease in older patients or patients with hepatic impairment and dosage reduction may be needed with these patients.

A study by Hand et

Summary

The sublingual buprenorphine–naloxone combination tablet provides an effective treatment for opiate addiction. The naloxone component does not appear to diminish the efficacy of buprenorphine. Naloxone absorption is minimal by this route. The sublingual absorption of buprenorphine is rapid, with peak plasma concentration occurring at 1 h after dosing. Increasing buprenorphine dose results in increasing plasma levels although this may not be dose-proportional, especially at higher doses. The

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