Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naı̈ve healthy male volunteers under a naltrexone block

McAleer, Sarah D.; Mills, Richard J.; Polack, Torsten; Hussain, Tanweer; Rolan, Paul; Gibbs, A. D.; Mullins, Frank G. P.; Hussein, Ziad

doi:10.1016/s0376-8716(03)00188-1

Cited by 48 publications

(58 citation statements)

References 12 publications

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“…As a result, tablets produce 50% of the buprenorphine levels that liquid preparations provide [47]. Sublingual bioavailability is 51% compared to 27% by the buccal route [45]. Absorption by tablets is more variable and dependent upon oral pH and the amount of drug swallowed [30,48,49].…”

Section: Absorptionmentioning

confidence: 98%

“…Bioavailability by buccal and sublingual routes is 30-60% due to the avoidance of first-pass hepatic clearance [30,31]. Buccal and sublingual tissues also act as tissue reservoirs that both delay absorption and lead to sustained drug levels (although sustained levels may also be due to a large volume of distribution) [45]. There appears to be no dose limitations to sublingual absorption, as there is a dose linear response curve [30].…”

Section: Absorptionmentioning

confidence: 99%

“…Biexponential kinetics are enterohepatic largely due to recirculation. Buprenorphine is largely excreted into bile as a glucuronide, which is deconjugated in the colon by bacteria beta-glucuronidase and reabsorbed [17,45]. Coefficient of variations for individual drug levels (as measured by variability in AUC) range from 24 to 40% due to differences in entero-hepatic recirculation and CYP3A4 activity [46,49].…”

Section: Buprenorphine Half-life and Physicochemical Characteristicsmentioning

confidence: 99%

“…This is due to metabolism by CYP3A4 in the gastrointestinal tract and first-pass hepatic clearance. Intranasal bioavailability ranges between 21 and 46%, depending upon the duration of study [44,45]. Bioavailability by buccal and sublingual routes is 30-60% due to the avoidance of first-pass hepatic clearance [30,31].…”

Section: Absorptionmentioning

confidence: 99%

“…The time to maximum concentration (T max) occurs between 1/2 and 3 h postdose by sublingual and 20 min for intravenous. Concentrations decrease biexponentially, with the second peak occurring around 5 h [17,45,49]. Biexponential kinetics are enterohepatic largely due to recirculation.…”

Section: Buprenorphine Half-life and Physicochemical Characteristicsmentioning

confidence: 99%

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Buprenorphine in cancer pain

Davis

2005

Support Care Cancer

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Buprenorphine is a broad spectrum, highly lipophilic, and long-acting partial mu opioid receptor agonist that is noncross tolerant to other opioids. Buprenorphine can be given by several routes. Metabolism is through CYP3A4 and CYP2C8 and by conjugases. Constipation and sexual dysfunction appear to be less with buprenorphine than with other opioids. The recent development of a polymer matrix patch delivery system for buprenorphine prevents "dose dumping" and facilitates pain management in those unable to take oral analgesics. Sublingual buprenorphine has been combined with naloxone to prevent illicit conversion to parenteral administration. Buprenorphine has been used extensively to control cancer pain. In certain clinical situations, buprenorphine may have particular advantages over other opioids.

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Section: Absorptionmentioning

confidence: 98%

Section: Absorptionmentioning

confidence: 99%

Section: Buprenorphine Half-life and Physicochemical Characteristicsmentioning

confidence: 99%

Section: Absorptionmentioning

confidence: 99%

Section: Buprenorphine Half-life and Physicochemical Characteristicsmentioning

confidence: 99%

See 3 more Smart Citations

Buprenorphine in cancer pain

Davis

2005

Support Care Cancer

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Evaluation of Drug‐Drug Interaction Liability for Buprenorphine Extended‐Release Monthly Injection Administered by Subcutaneous Route

Kharidia

Howgate

Laffont

et al. 2021

Clinical Pharm in Drug Dev

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Buprenorphine extended-release (BUP-XR) formulation is a once-monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Buprenorphine undergoes extensive cytochrome P450 (CYP) 3A4 metabolism, leading to potential drug-drug interactions (DDIs) as reported for sublingual buprenorphine. Sublingual buprenorphine is subject to first-pass extraction, as a significant proportion of the dose is swallowed. Because subcutaneous administration avoids first-pass extraction, the DDI with CYP3A4 inhibitors is expected to be less than the 2-fold increase reported for the sublingual route. The objective of this analysis was to predict the magnitude of DDI following coadministration of BUP-XR with a strong CYP3A4 inhibitor or inducer using physiologically based pharmacokinetic (PBPK) modeling. Models were developed and verified by comparing predicted and observed data for buprenorphine following intravenous and sublingual dosing. Comparison of predicted and observed pharmacokinetic (PK) profiles and PK parameters demonstrated acceptable predictive performance of the models (within 1.5-fold). Buprenorphine plasma concentrations following administration of a single dose of BUP-XR (300 mg) were simulated using a series of intravenous infusions. Daily coadministration of strong CYP3A4 inhibitors with BUP-XR predicted mild increases in buprenorphine exposures (AUC, 33%-44%; C max , 17-28%). Daily coadministration of a strong CYP3A4 inducer was also associated with mild decreases in buprenorphine AUC (28%) and C max (22%). In addition, the model predicted minimal increases in buprenorphine AUC (8%-11%) under clinical conditions of 2 weeks' treatment with CYP3A4 inhibitors administered after initiation of BUP-XR. In conclusion, the PBPK predictions indicate that coadministration of BUP-XR with strong CYP3A4 inhibitors or inducers would not result in clinically meaningful interactions.

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Physiologically‐Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome

Hoogdalem

Johnson²,

McPhail

et al. 2021

Clin Pharma and Therapeutics

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Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC 0-∞ ), peak concentration (C max ), and time to reach peak concentration (T max ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

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Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naı̈ve healthy male volunteers under a naltrexone block

Cited by 48 publications

References 12 publications

Buprenorphine in cancer pain

Buprenorphine in cancer pain

Evaluation of Drug‐Drug Interaction Liability for Buprenorphine Extended‐Release Monthly Injection Administered by Subcutaneous Route

Physiologically‐Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome

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