Plasma Concentrations Of Norbuprenorphine Research Articles

Response to the Letter to the Editor by Dr. Srinivas on the recent publication of Al-Tawil et al. on the pharmacokinetics of transdermal buprenorphine patch in the elderly

To the Editor, We are writing in response to the letter from Dr. Srinivas commenting on the recent publication by Al-Tawil et al. on the pharmacokinetics of transdermal buprenorphine patch in the elderly [1]. We represent the authors and Mundipharma Research Ltd., the Clinical Pharmacology group of which, Helen Johnson (a co-author) in particular, was responsible for the pharmacokinetic analysis carried out in this study. The study reported comparable systemic exposures of buprenorphine and norbuprenorphine in two groups of elderly (≥ 75 years) and younger (50–60 years) individuals, leading to the conclusion that no dosage alterations are necessary for pharmacokinetic (PK) reasons when treating elderly people with buprenorphine transdermal patches. We are surprised that Dr. Srinivas has elected to extrapolate from the average PK data that were reported in the article, based on the qualitatively (but not significantly) higher norbuprenorphine plasma concentrations in the elderly group, and subsequently to speculate that this may contribute to several safety issues, including respiratory depression. In response, we wish to provide a more detailed illustration of the data generated in this study. The following figures illustrate the distribution of individual subject area under the curve values associated with buprenorphine and norbuprenorphine in the two study groups (Figs. ​(Figs.11 and ​and22). Fig. 1 Area under the plasma concentration-time curve at steady state (AUCtau) buprenorphine, data points are individual participant values Fig. 2 Area under the plasma concentration-time curve at steady state (AUCtau) norbuprenorphine, data points are individual participant values These figures demonstrate very clearly that the ranges of exposure of both compounds were highly comparable between the groups, and illustrate why there were no significant differences recorded, or even hinted at, in the original analysis. The spread and overlap of individual Cmin and Cmax steady state data are also comparable between the two groups for both analytes, further reinforcing the primary conclusion. As stated in the original article, more adverse events (216) were actually recorded in the younger group than in elderly participants (164). We have provided the data in more detail to support the original scientific findings. In so doing, we believe that we have demonstrated that there is no basis for the speculative text regarding norbuprenorphine and its safety profile in the elderly. Yours sincerely, Helen E Johnson (Clinical Pharmacokineticist) and Anna-Carin Berggren (Medical Affairs Manager).

Buprenorphine assay and plasma concentration monitoring in HIV-infected substance users

The availability of buprenorphine (BUP) provides an alternative approach to the treatment of opioid addiction with methadone, an agent that has many drug–drug interactions when combined with antiretroviral therapy (ART). However, due to limited long-term pharmacokinetic studies in HIV-infected patients, the clinical use of BUP, a CYP450-3A4 substrate, will require that studies be conducted to examine safety, tolerability and pharmacokinetics when these drugs are taken for chronic treatment. One clinical approach could include plasma concentration monitoring to avoid under- or overdosing BUP secondary to drug interactions with ART. The measurement of BUP and its active metabolite, norbuprenorphine (NBUP) facilitates the addition of BUP to ART in an attempt to avoid drug toxicity as described in a recent report by Bruce et al. Therefore, our objective was to validate a BUP assay and integrate its application into an ongoing antiretroviral (ARV) plasma concentration monitoring program. A chromatographic method for monitoring BUP and its active metabolite, NBUP was investigated. An assay was developed that would facilitate BUP and ARV measurement from a single 3 mL blood sample (0.75 mL plasma required) in conjunction with a previously validated multiple ARV HPLC method. The method measures BUP and NBUP over the range from 0.25 to 50 ng/mL with mass spectrometry detection. Inter- and intra-assay variation was ≤11%, across the concentration range. The method quantitates BUP and NBUP plasma concentrations within the range of expected values from current BUP dosing guidelines. Use of this combined BUP and ARV plasma concentration monitoring approach for a representative patient receiving BUP, atazanavir and efavirenz demonstrated its clinical application.

An injection depot formulation of buprenorphine: extended biodelivery and effects

Buprenorphine is an effective medication for treatment of opioid dependence. An injectable depot formulation of buprenorphine has been developed using biodegradable polymer microcapsule technology. This formulation may offer effective treatment of opioid dependence and enhance treatment delivery while minimizing risks of patient non-adherence or illicit diversion of the medication. This report provides a characterization of the bio-delivery of this injectable depot in humans and of the relationship of drug blood levels to pharmacodynamic indices. The data are from two studies in which 11 opioid-dependent volunteers each received a single depot injection containing 58 mg of buprenorphine, and include previously unreported detailed plasma concentration data over a 6-week time-course following depot administration and examination of their relationship to pharmacodynamic indices. Mean plasma buprenorphine increased gradually following depot administration, peaked at 2-3 days with a mean concentration of 1.25 ng/ml and then decreased gradually, approaching undetectable levels (< 0.10 ng/mL) by 6 weeks. There was substantial between-subject consistency in several aspects of buprenorphine bio-delivery, including time to first detectable blood level (4 hours), peak blood level (2 days) and undetectable blood level (6-6.5 weeks). In contrast, there was marked between-subject variability in the magnitude of peak buprenorphine concentrations, ranging from 0.17 to 3.47 ng/ml. Extent of opioid blockade was tested by weekly opioid challenges with 3 mg subcutaneous hydromorphone; subjective response and pupillary constriction were related inversely to both buprenorphine and norbuprenorphine plasma concentrations (r=0.84-0.95). The data document that this depot formulation provides effective buprenorphine delivery for several weeks and that effects persist even at fairly low buprenorphine plasma concentrations. Suggestions are offered for further research needed to develop this formulation for clinical use as a detoxification and/or maintenance pharmacotherapy for opioid dependence.

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R = 0.74; P < 0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 μg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine

Filitz, J.; Grieinger, N.ß; Sittl, R.; Likar, R.; Schüttler, J.; Koppert, W. Author Information

Lack of effect of CYP3A4 inhibitor ketoconazole on transdermally administered buprenorphine

Objective To evaluate the effect of ketoconazole on the pharmacokinetics of buprenorphine and its metabolites following application of a 10-mg buprenorphine transdermal system (BTDS). Methods This was a randomized, double-blind, 2-treatment, 2-period crossover study with 20 healthy male and female subjects. Treatments: BTDS for 7 days with ketoconazole (200 mg po, bid) or placebo in crossover fashion. Results The 90% confidence intervals for the estimated ratios of population geometric means for buprenorphine AUCt and Cmax were within 80% to 125%. Plasma concentrations of norbuprenorphine, and norbuprenorphine glucuronide, were detected in both treatments and were not lower in the BTDS+ ketoconazole treatment. Plasma concentrations of buprenorphine-3-glucuronide were measurable in 5 out of 18 BTDS+ ketoconazole subjects. No apparent safety concerns were identified. Eight subjects had hyperpigmentation at the application site (4 events were resolved and 4 were continuing). Conclusions Plasma concentrations of buprenorphine from BTDS did not differ during co-medication with ketoconazole 200 mg bid vs. placebo. BTDS dose adjustment is not needed for subjects taking concomitant CYP3A4 inhibitors. Clinical Pharmacology & Therapeutics (2005) 77, P78–P78; doi: 10.1016/j.clpt.2004.12.188