Pharmacokinetics and Pharmacodynamics of Multiple Sublingual Buprenorphine Tablets in Dose‐Escalation Trials

Abstract

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Using buprenorphine short-term taper to facilitate early treatment engagement

“…This observation is consistent with recent dose-escalation studies suggesting that there is a bceilingQ effect for BNX resulting in a lack of dose-proportional increases in effects for higher dose ranges (Ciraulo et al, 2006).…”

An evidence-based recommendation to increase the dosing frequency of buprenorphine during pregnancy

“…Details of the development and validation of the model are discussed elsewhere 11 . In summary, after developing a PBPK model from IV buprenorphine, we utilized data from Ciraulo et al 12 for building a sublingual model for the 8 mg dose. The sublingual model was assessed at doses of 4, 8, 16 and 24 mg. for intra-study validation Model naïve data from Harris et al 13 and McAlear et al 14 were used for the inter-study validation of the buprenorphine sublingual PBPK.…”

“…The half-life of SL buprenorphine in non- pregnant subjects is long and in one study ranged from 24–69 hours and this has led to the strategy of once daily or even less frequent dosing 6,7 . Even in non-pregnant subjects the plasma concentrations after a single 24 mg daily dose decrease rapidly and are lower than 1ng/ml within 12 hours of drug administration 12 . There are limited data describing the half-life of buprenorphine in pregnancy.…”

Spotlight on Buprenorphine/Naloxone in the Treatment of Opioid Dependence†

“…[3][4][5][6][7][8] Opioid agonist effects of buprenorphine are less than the maximal effects of full opioid agonists, such as morphine, and are limited by a 'ceiling' effect. [7,9,10] The drug may produce a lower degree of physical dependence than full opioid agonists (e.g. heroin, morphine or methadone).…”