Pharmacokinetics, bioavailability and opioid effects of liquid versus tablet buprenorphine
Introduction
The availability of buprenorphine for the outpatient treatment of opioid addiction (Resnick, 2003) represents a landmark event in the field of addiction treatment in the United States. Scheduled so that it may be dispensed by physicians in their private offices, buprenorphine is the first real alternative to the methadone clinic available to patients seeking pharmacologic treatment for addiction to heroin or prescription opioids (Leshner, 2003, Ling and Smith, 2002). After nearly eight decades, US physicians are able to again use an opioid to treat patients with opioid addiction, despite buprenorphine for this indication having been available considerably longer in Australia and in Europe, most notably in France where it had been approved since 1995. Multiple carefully controlled clinical trials have established the dosing parameters, unique safety and good efficacy of buprenorphine (Barnett et al., 2001, Giacomuzzi et al., 2003, Ling and Wesson, 2003, West et al., 2000). Due to its partial agonist properties, a ceiling effect exists for its agonist properties, and unlike methadone or LAAM, it produces what appears to be a low level of physical dependence with minimal withdrawal symptoms (Walsh and Eissenberg, 2003).
As currently marketed, buprenorphine is formulated as a sublingual (SL) tablet in two forms, a mono-product (Subutex®) containing buprenorphine alone, and a combination product (Suboxone®) combined with naloxone to discourage parenteral misuse. Most of the studies conducted by European and Australian investigators had used the tablet mono-product Subutex® and most recent studies by US investigators had used the combination tablet Suboxone®. The bulk of the early investigations, mostly conducted in the US, and the pivotal clinical trials supporting buprenorphine's approval by the US Food and Drug Administration (FDA) were conducted using a SL solution, which is known to be not strictly bioequivalent to the tablet formulation (Walsh and Eissenberg, 2003).
Previous single-dose pharmacokinetic (PK) studies comparing buprenorphine sublingual tablets with solution formulations have shown that the extent of bioavailability of the tablet formulation (8 mg) was quantitatively less than that of the solution formulation (8 mg/ml) (Nath et al., 1999). The bioavailability of one 8 mg buprenorphine sublingual tablet was approximately 50% (range 24–74%) relative to 1 ml of 8 mg/ml buprenorphine sublingual solution, and unrelated to salivary pH. In comparison to the liquid, the tablet also produced significantly fewer opiate agonist effects, although the same degree of opioid antagonist effects. Similarly, in two studies using more chronic dosing paradigms, plasma concentrations of the 8 mg tablet were estimated to be 55% of those of the solution after 7 days of dosing (Schuh and Johanson, 1999), and 62% after 14 days of dosing (Strain et al., 2004).
The present study was designed to test the estimated 50% relative bioavailability for the tablet in comparison to the solution, as demonstrated in acute- and chronic-dose studies. Evaluated were the steady-state pharmacokinetics and bioavailability of buprenorphine following multiple administrations (10 days) of two 8 mg buprenorphine SL tablets in comparison to 1 ml of 8 mg/ml SL solution. Further, evidence of physiological, subjective and objective opioid agonist and antagonist responses to the tablets versus solution was documented.
Section snippets
Design
The study used an open-label, randomized, two-way crossover design and was conducted in an inpatient setting over 21 days. Twenty-four subjects were randomized to receive one of two treatments (two 8 mg tablets SL QD or 1 ml of 8 mg/ml solution SL QD) for the first 10-day period and the other treatment for the second 10-day period with no washout period between treatments. Plasma samples for PK analysis were taken prior to dosing Days 7–10 of each treatment period, and at specified intervals for 24
Results
A total of 34 subjects enrolled in the study; of the 10 subjects who discontinued prematurely, 4 withdrew at their own request and 6 were discharged due to protocol non-compliance. Adverse event data were collected from the nine discharged subjects who had received at least one dose of buprenorphine. Demographic characteristics of 24 subjects who completed the study are summarized in Table 1.
Discussion
Although most of the early clinical studies of buprenorphine for the treatment of opioid addiction had been conducted by US investigators, its approval by the US Food and Drugs Administration (FDA) was slow. It literally took an act of congress in the form of the Narcotic Treatment Act of 2000 to make buprenorphine available to US clinicians. In Europe, notably in France and in Australia, buprenorphine for treatment of opioid addiction has been available considerably longer, and a number of
Acknowledgements
This work was supported by a medication development center grant from NIDA. Reckitt/Benckiser, manufacturer and owner of buprenorphine products provided the study material for this study. Walter Ling has served as consultant to Reckitt/Benckiser and Reckitt/Benckiser has given UCLA an unrestricted educational grant to support his work. The analytical work was performed under funding from the National Institutes on Drug Abuse, National Institutes of Health Contract No. N01DA-1-9205 and
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