Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

Abstract

Background Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7±0.7 μg/L) after 16 mg IV administration. Conclusions Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg.

A physiologically based pharmacokinetic modelling approach to predict buprenorphine pharmacokinetics following intravenous and sublingual administration

“…The predicted concentration–time profile of the final BUP PBPK model following an 8 mg IV BUP dose was within the range of the observed data published by Huestis et al . . The predicted means of the concentration–time profiles and 90% PI overlaid with the observed data for the first 24 h of the 72‐h dataset are shown in Figure .…”

“…The 72‐h PK profile from Huestis et al . was used for model development (8 mg) and intrastudy validation (2, 4, 12 and 16 mg). One hundred virtual healthy subjects, spread over 10 trials, were used for each PBPK simulation.…”

Gestational changes in buprenorphine exposure: A physiologically‐based pharmacokinetic analysis

“…Plasma clearance of BUP in healthy volunteers is around 60 l h –1 after an IV injection . Comparing the clearance of BUP with hepatic blood flow in healthy subjects (1.5 l min –1 ), the estimated BUP hepatic extraction ratio is ∼0.67, which indicates BUP to be an intermediate to high hepatic clearance drug.…”

High-sensitivity analysis of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in plasma and urine by liquid chromatography–mass spectrometry

“…Buprenorphine is commonly administered sublingually at 4–32 mg/d for addiction maintenance therapy, with steady-state plasma buprenorphine concentrations averaging 5–10 ng/mL, and 2–16 mg intravenous buprenorphine results in peak buprenorphine and norbuprenorphine concentrations of 20–130 and 0.5–3.5 ng/mL respectively [43]. In contrast, lower doses (0.15–0.2 mg intravenously, 2 mg sublingually) must be used in non-dependent healthy volunteers [44].…”