Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Pharmacokinetics of intravenous, oral transmucosal, and intranasal buprenorphine in healthy male dogs.

Effective management of pain in animals is of critical importance but options are limited for treating acute pain in dogs on an outpatient basis. The objective of this study was to compare the plasma concentrations and pharmacokinetics of a concentrated solution of buprenorphine, 1.8 mg/ml (Simbadol™) administered intravenously, intranasally, and via the oral transmucosal (OTM) route in healthy male dogs. Five healthy castrated adult male Beagle-cross dogs were included in this randomized blocked crossover study. The dogs received 0.03 mg/kg body weight buprenorphine intravenously, intranasally, or via the OTM route, with a minimum 72-h washout period between treatments. Blood samples were collected at multiple intervals up to 24 h post administration and buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. Non-compartmental pharmacokinetic analysis revealed that the area under the curve of intravenous, intranasal, and OTM routes were 28.0 (15.1-41.3) h × ng/ml, 16.1 (3.4-28.7) h × ng/ml and 10.8 (8.8-11.8) h × ng/ml, respectively. The bioavailability of intranasal and OTM routes were 57.5 (22.7-93.7)% and 41.1 (25.5-69.4)%, respectively. Intranasal and OTM routes of administration of concentrated buprenorphine in dogs may allow for the provision of analgesic care at home.

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients.

BACKGROUND: Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression. METHODS: In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded. RESULTS: Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001). INTERPRETATION: Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

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

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 (AUC0-∞ ), peak concentration (Cmax ), and time to reach peak concentration (Tmax ) 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.

Physiologically based pharmacokinetic modelling in pregnancy: Model reproducibility and external validation.

AIMS: Physiologically based pharmacokinetic (PBPK) models have been previously developed for betamethasone and buprenorphine for pregnant women. The goal of this work was to replicate and reassess these models using data from recently completed studies. METHODS: Betamethasone and buprenorphine PBPK models were developed in Simcyp V19 based on prior publications using V17 and V15. Ability to replicate models was verified by comparing predictions in V19 to those previously published. Once replication was verified, models were reassessed by comparing predictions to observed data from additional studies in pregnant women. Model performance was based upon visual inspection of concentration vs. time profiles, and comparison of pharmacokinetic parameters. Models were deemed reproducible if parameter estimates were within 10% of previously reported values. External validations were considered acceptable if the predicted area under the concentration-time curve (AUC) and peak plasma concentration fell within 2-fold of the observed. RESULTS: The betamethasone model was successfully replicated using Simcyp V19, with ratios of reported (V17) to reproduced (V19) peak plasma concentration of 0.98-1.04 and AUC of 0.95-1.07. The model-predicted AUC ratios ranged from 0.98-1.79 compared to external data. The previously published buprenorphine PBPK model was not reproducible, as we predicted intravenous clearance of 70% that reported previously (both in Simcyp V15). CONCLUSION: While high interstudy variability was observed in the newly available clinical data, the PBPK model sufficiently predicted changes in betamethasone exposure across gestation. Model reproducibility and reassessment with external data are important for the advancement of the discipline. PBPK modelling publications should contain sufficient detail and clarity to enable reproducibility.

Mechanisms of respiratory depression induced by the combination of buprenorphine and diazepam in rats.

BACKGROUND: The safety profile of buprenorphine has encouraged its widespread use. However, fatalities have been attributed to benzodiazepine/buprenorphine combinations, by poorly understood mechanisms of toxicity. Mechanistic hypotheses include (i) benzodiazepine-mediated increase in brain buprenorphine (pharmacokinetic hypothesis); (ii) benzodiazepine-mediated potentiation of buprenorphine interaction with opioid receptors (receptor hypothesis); and (iii) combined effects of buprenorphine and benzodiazepine on respiratory parameters (pharmacodynamic hypothesis). METHODS: We studied the neuro-respiratory effects of buprenorphine (30 mg kg-1, i.p.), diazepam (20 mg kg-1, s.c.), and diazepam/buprenorphine combination in rats using arterial blood gas analysis, plethysmography, and diaphragm electromyography. Pretreatments with various opioid and gamma-aminobutyric acid receptor antagonists were tested. Diazepam impact on brain 11C-buprenorphine kinetics and binding to opioid receptors was studied using positron emission tomography imaging. RESULTS: In contrast to diazepam and buprenorphine alone, diazepam/buprenorphine induced early-onset sedation (P<0.05) and respiratory depression (P<0.001). Diazepam did not alter 11C-buprenorphine brain kinetics or binding to opioid receptors. Diazepam/buprenorphine-induced effects on inspiratory time were additive, driven by buprenorphine (P<0.0001) and were blocked by naloxonazine (P<0.01). Diazepam/buprenorphine-induced effects on expiratory time were non-additive (P<0.001), different from buprenorphine-induced effects (P<0.05) and were blocked by flumazenil (P<0.01). Diazepam/buprenorphine-induced effects on tidal volume were non-additive (P<0.01), different from diazepam- (P<0.05) and buprenorphine-induced effects (P<0.0001) and were blocked by naloxonazine (P<0.05) and flumazenil (P<0.05). Compared with buprenorphine, diazepam/buprenorphine decreased diaphragm contraction amplitude (P<0.01). CONCLUSIONS: Pharmacodynamic parameters and antagonist pretreatments indicate that diazepam/buprenorphine-induced respiratory depression results from a pharmacodynamic interaction between both drugs on ventilatory parameters.

Buprenorphine: Far Beyond the "Ceiling".

Chronic pain, including neuropathic pain, represents an untreated disease with important repercussions on the quality of life and huge costs on the national health system. It is well known that opioids are the most powerful analgesic drugs, but they represent the second or third line in neuropathic pain, that remain difficult to manage. Moreover, these drugs show several side effects that limit their use. In addition, opioids possess addictive properties that are associated with misuse and drug abuse. Among available opioids compounds, buprenorphine has been suggested advantageous for a series of clinical reasons, including the effectiveness in neuropathic pain. Some properties are partly explained by its unique pharmacological characteristics. However, questions on the dynamic profile remain to be answered. Pharmacokinetics optimization strategies, and additional potentialities, are still to be explored. In this paper, we attempt to conceptualize the potential undiscovered dynamic profile of buprenorphine.

Pharmacokinetics of a high-concentration formulation of buprenorphine (Simbadol) in male dogs.

OBJECTIVE: To describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: A total of six healthy male intact Beagle dogs, aged 9-13 months and weighing 10.3 ± 1.4 kg (mean ± standard deviation). METHODS: Dogs were randomized to be administered buprenorphine (0.12 mg kg-1; Simbadol, 1.8 mg mL-1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography-tandem mass spectrometry. RESULTS: A three-compartment model with zero or biphasic rapid and slow first-order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first-order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg-1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute-1 kg-1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minute delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80-239)%. Calculated terminal half-life was 963 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: The high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues.

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

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%; Cmax , 17-28%). Daily coadministration of a strong CYP3A4 inducer was also associated with mild decreases in buprenorphine AUC (28%) and Cmax (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.

Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection.

Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 µg/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 µg/L and 0.04 µg/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum-maximum), were Cmax 4.31 µg/L (1.93-15.5), AUCinf 2.89 h*µg/L (1.72-40.2), CL 3.39 L/h/kg (0.25-6.02), terminal t½ 1.75 h (1.07-31.0), Vss 8.04 L/kg (1.05-49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half-lives for six subjects, and a wide between-subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans.

High-Performance Liquid Chromatography-Tandem Mass Spectrometry for Buprenorphine Evaluation in Plasma-Application to Pharmacokinetic Studies in Rabbits.

The precise and reliable determination of buprenorphine concentration is fundamental in certain medical or research applications, particularly in pharmacokinetic studies of this opioid. The main challenge is, however, the development of an analytical method that is sensitive enough, as the detected in vivo concentrations often fall in very low ranges. Thus, in this study we aimed at developing a sensitive, repeatable, cost-efficient, and easy HPLC analytical protocol for buprenorphine in rabbit plasma. In order to obtain this, the HPLC-MS2 system was used to elaborate and validate the method for samples purified with liquid-liquid extraction. Fragment ions 468.6→396.2 and 468.6→414.2 were monitored, and the method resulted in a high repeatability and reproducibility and a limit of quantification of 0.25 µg/L with a recovery of 98.7-109.0%. The method was linear in a range of 0.25-2000 µg/L. The suitability of the analytical procedure was tested in rabbits in a pilot pharmacokinetic study, and it was revealed that the method was suitable for comprehensively describing the pharmacokinetic profile after buprenorphine intravenous administration at a dose of 300 µg/kg. Thus, the method suitability for pharmacokinetic application was confirmed by both the good validation results of the method and successful in vivo tests in rabbits.

Pharmacokinetics of Buprenorphine and Sustained-release Buprenorphine in Common Marmosets (Callithrix jacchus).

Buprenorphine is an essential component of analgesic protocols in common marmosets (Callithrix jacchus). The use of buprenorphine HCl (BUP) and sustained-release buprenorphine (BSR) formulations has become commonplace in this species, but the pharmacokinetics have not been evaluated. Healthy adult (age, 2.4 to 6.8 y; 6 female and 6 male) common marmosets were enrolled in this study to determine the pharmacokinetic parameters, plasma concentration-time curves, and any apparent adverse effects of these compounds. Equal numbers of each sex were randomly assigned to receive BUP (0.02 mg/kg IM) or BSR (0.2 mg/kg SC), resulting in peak plasma concentrations (mean ± 1 SD) of 15.2 ± 8.1 and 2.8 ± 1.2 ng/mL, terminal phase t1/2 of 2.2 ± 1.0 and 32.6 ± 9.6 h, and AUC0-last of 16.1 ± 3.7 and 98.6 ± 42.7 ng × h/mL. The plasma concentrations of buprenorphine exceeded the proposed minimal therapeutic threshold (0.1 ng/mL) at 5 and 15 min after BUP and BSR administration, showing that both compounds are rapid-acting, and remained above that threshold through the final time points of 8 and 72 h. Extrapolation of the terminal elimination phase of the mean concentration-time curves was used to develop the clinical dosing frequencies of 6 to 8 h for BUP and 3.0 to 3.5 d for BSR. Some adverse effects were observed after the administration of BUP to common marmosets in this study, thus mandating judicious use in clinical practice. BSR provided a safe, long-acting option for analgesia and therefore can be used to refine analgesic protocols in this species.

Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches.

Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first-line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

Bioavailability of subcutaneous and intramuscular administrated buprenorphine in New Zealand White rabbits.

BACKGROUND: Buprenorphine is one of the most used analgesics for postoperative pain in rabbits. The recommended dose in rabbits (0.01-0.05 mg/kg) is the same for intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration, despite lack of pharmacokinetic data. Five male and five female New Zealand White rabbits (mean ± SD body weight 3.1 ± 0.3 kg) were administered 0.05 mg/kg buprenorphine by the IV, IM and SC routes and 0.1 mg/kg by the SC route, in a cross-over design with two-week wash-out periods between treatments. Blood was collected before, and up to 8 h post buprenorphine injection, for determination of serum levels by UPHLC-MS/MS. RESULTS: The area under the time concentration curve (AUC0-t) was lower after SC (398 ± 155 ng/mL/min) than IM (696 ± 168 ng/mL/min, p < 0.001) and IV (789 ± 189 ng/mL/min, p < 0.001) administration. The maximum serum concentration was lower after SC (2.2 ± 1.4 ng/mL) than after IM (11 ± 3.2 ng/mL) administration (p < 0.001). The bioavailability was lower after SC (50 ± 19%) than after IM (95 ± 21%) administration (p = 0.006). The elimination half-life was longer after SC (260 ± 120 min) than after IM (148 ± 26 min, p = 0.002) as well as IV (139 ± 33 min) injection (p < 0.001). An increase in the SC dose from 0.05 to 0.1 mg/kg resulted in an increase in the area under the time concentration curve of 50% in female (p = 0.022) and 165% in male rabbits (p < 0.001). The bioavailability did not change in the females (36 ± 14%, p = 0.6), whereas it increased in the males (71 ± 23%, p = 0.008). CONCLUSIONS: The lower bioavailability of 0.05 mg/kg buprenorphine after SC administration could explain the lack of efficacy seen in clinical pain studies in rabbits, using this route. For immediate pain relief, IV or IM administration is therefore be recommended, whereas SC administration may be useful to sustain analgesic serum levels, once efficient pain relief has been achieved. The current data do not support an increase in dose to compensate for the lower SC bioavailability.

Effect of Sleeve Gastrectomy on Buprenorphine Pharmacokinetics: A Planned Case Observation.

PURPOSE: Bariatric surgery may affect the absorption and metabolism of drugs by various mechanisms. We present a planned case observation of a patient treated with sublingual buprenorphine in an opioid maintenance treatment program, and the observed changes in buprenorphine pharmacokinetics following gastric sleeve surgery. METHODS: Serial blood samples during a dose interval of 24 hours were obtained approximately 1 year preoperatively as well as 1 week, 1 month and 12 months postoperatively and key pharmacokinetic variables were calculated. FINDINGS: The systemic exposure of buprenorphine (AUC) was relatively stable from the preoperative sampling to 1 week postoperatively (-6.3%), but declined markedly at 1 month (-43%) and 12 months (-42%) postoperatively. The maximum concentration of buprenorphine almost doubled at 1 week postoperatively before returning to baseline values 1 month and 12 months postoperatively. IMPLICATIONS: This case observation indicates that after sleeve gastrectomy, the systemic exposure of sublingual buprenorphine can decrease. Clinicians should be aware of the possibility of loss of effect and emerging abstinence symptoms following sleeve gastrectomy. We recommend monitoring the patient closely for abstinence symptoms postoperatively and considering measuring serum concentrations of buprenorphine pre- and postoperatively.

Scalable in silico Simulation of Transdermal Drug Permeability: Application of BIOiSIM Platform.

INTRODUCTION: Transdermal drug delivery is gaining popularity as an alternative to traditional routes of administration. It can increase patient compliance because of its painless and noninvasive nature, aid compounds in bypassing presystemic metabolic effects, and reduce the likelihood of adverse effects through decreased systemic exposure. In silico physiological modeling is critical to predicting dermal exposure for a therapeutic and assessing the impact of different formulations on transdermal disposition. METHODS: The present study aimed at developing a physiologically based transdermal platform, "BIOiSIM", that could be globally applied to a wide variety of compounds to predict their transdermal disposition. The platform integrates a 16-compartment model of compound pharmacokinetics and was used to simulate and predict drug exposure of three chemically and biologically distinct drug-like compounds. Machine learning optimization was composed of two components: exhaustive search algorithm (coarse-tuning) and descent (fine-tuning) integrated with the platform used to quantitatively determine parameters influencing pharmacokinetics (eg permeability, kperm) of test compounds. RESULTS: The model successfully predicted drug exposure (AUC, Cmax and Tmax) following transdermal application of morphine, buprenorphine and nicotine in human subjects, mostly with less than two-fold absolute average fold error (AAFE). The model was further able to successfully characterize the relationship between observed systemic exposure and intended pharmacological effect. The predicted systemic concentration of morphine and plasma levels of endogenous pain biomarkers were used to estimate the effectiveness of a given therapeutic regimen. CONCLUSION: BIOiSIM marks a novel approach to in silico prediction that will enable leveraging of machine learning technology in the pharmaceutical space. The approach to model development outlined results in scalable, accurate models and enables the generation of large parameter/coefficient datasets from in vivo clinical data that can be used in future work to train quantitative structure activity relationship (QSAR) models for predicting likelihood of compound utility as a transdermally administered therapeutic.

Pharmacokinetics and analgesic effects of intravenous, intramuscular or subcutaneous buprenorphine in dogs undergoing ovariohysterectomy: a randomized, prospective, masked, clinical trial.

BACKGROUND: Buprenorphine is used for canine postoperative pain management. This study aimed to describe the pharmacokinetics and evaluate the analgesic efficacy of buprenorphine (Simbadol, 1.8 mg/mL) administered by different routes in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, masked, clinical trial. Buprenorphine (0.02 mg/kg) was administered intravenously (IV), intramuscularly (IM) or subcutaneously (SC) (n = 8/group) 0.5 h before general anesthesia with propofol-isoflurane. Carprofen (4.4 mg/kg SC) was administered after anesthetic induction and before ovariohysterectomy. Pain was scored using the short-form Glasgow composite pain scale for dogs (SF-GCPS). Dogs were administered morphine (0.25 mg/kg IV) when SF-GCPS scores were ≥ 5/20. Blood sampling was performed up to 720 min after drug administration. Plasma buprenorphine and norbuprenorphine concentrations were analyzed using liquid chromatography mass spectrometry. Pharmacokinetics of buprenorphine was described using a non-compartmental model (PK Solver 2.0). Statistical analysis was performed using linear mixed models and Fisher's exact test (p < 0.05). RESULTS: Pain scores were significantly higher than baseline after IV (0.5-2 h), IM (0.5-3 h) and SC (0.5-4 h) but not among groups. Prevalence of rescue analgesia was significantly higher in SC (7/8 dogs) than IV (2/8) but not different between IV and IM (3/8) or IM and SC. The frequency of rescue analgesia was not significantly different among groups (IV = 2, IM = 5 and SC = 9). Norbuprenorphine was not detected. For IV, IM and SC administration, clearance was 1.29, 1.65 and 1.40 L/hour/kg, volume of distribution was 6.8, 14.2 and 40.1 L/kg, the elimination half-life was 3.7, 5.7, 22 h, and the area under the plasma concentration-time curved extrapolated to infinity was 15.7, 12.4 and 16.4 ng/mL/hour, respectively. Bioavailability for IM and SC was 62.6 and 40%, respectively. Maximum plasma concentrations of buprenorphine were 6.2 and 1.3 ng/mL at 0.14 and 0.33 h after IM and SC administration, respectively. CONCLUSIONS: The route of administration influences the analgesic efficacy of buprenorphine in dogs. SC administration of buprenorphine failed to provide clinical analgesia due to erratic drug absorption. At the doses administered, the IV and IM routes are preferred for postoperative analgesia.

New method of creating hybrid of buprenorphine loaded rifampin/polyethylene glycol/alginate nanoparticles.

An indicator for cytochrome P450 enzymes which have the most fundamental role in methadone metabolism in the liver. In this study preparation in vitro, in vivo release and biological activities of Fe3O4@ZnO/rifampin/polyethylene glycol/buprenorphine/alginate nanoparticles investigated. Rifampin is activator for the cytochrome P-3 enzymes which can detoxify residual drugs in the liver. This paper examines the changes pH, absorption rate, drug release, in vivo test (30 rats) in selected Wistar rats. All rats were either orally addicted to morphine after 21 days. After establishing dependence based on an observation of behavioral parameters the ability to quit the new drug was evaluated. In vitro and in vitro tests on antibacterial activity and multiple intestinal inflammation in addicts were conducted. Recent drug delivery systems that use polymers cause more sustainability of drug in the body and also prevent drug interactions. This research showed the success of decreasing consumption dose of the drug from 0.004 to 0.0005 mg, increasing lifetime from 24 to 32 h to 72-96 h, and decreasing the number of hepatic tissues that were damaged. The results of this investigation were confirmed by clinical tests and the dyeing process of mason tri­chromium and hematoxylin and eosin.

Pregnancy Alters CYP- and UGT-Mediated Metabolism of Buprenorphine.

BACKGROUND: In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug Administration, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics (PKs). Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than after pregnancy. The mechanism(s) responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)-mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation. METHODS: Data from 2 clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, nonrandomized longitudinal BUP PK study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to 3 studies during and after pregnancy (the second, third trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (first, second-half of pregnancy), as well as during the postpartum period. In addition, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected before a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 hours or till the end of the dosing interval. Plasma concentrations of BUP and 3 metabolites were quantified using validated ultraperformance liquid chromatography-tandem mass spectrometric assays. RESULTS: In total, 19, 18, and 14 subjects completed the PK study during 1/2 trimester, third trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the first and second, third trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at first/second trimesters, third trimester, and postpartum, respectively. Linear mixed-effect modeling analysis indicated that the AUC ratios of CYP- and UGT-mediated metabolism of BUP were significantly higher during pregnancy compared with postpartum. CONCLUSIONS: The CYP and UGT activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared with the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in nonpregnant subjects.

Monitoring Prenatal Exposure to Buprenorphine and Methadone.

PURPOSE: Buprenorphine and methadone are international gold standards for managing opioid use disorders. Although they are efficacious in treating opioid dependence, buprenorphine and methadone present risks, especially during pregnancy, causing neonatal abstinence syndrome and adverse obstetrical outcomes. Buprenorphine and methadone are also abused during pregnancy, and identifying their use is important to limit unprescribed prenatal exposure. Previous studies have suggested that concentrations of buprenorphine, but not methadone markers in unconventional matrices may predict child outcomes, although currently only limited data exist. We reviewed the literature on concentrations of buprenorphine, methadone, and their metabolites in unconventional matrices to improve data interpretation. METHODS: A literature search was conducted using scientific databases (PubMed, Scopus, Web of Science, and reports from international institutions) to review published articles on buprenorphine and methadone monitoring during pregnancy. RESULTS: Buprenorphine and methadone and their metabolites were quantified in the meconium, umbilical cord, placenta, and maternal and neonatal hair. Methadone concentrations in the meconium and hair were typically higher than those in other matrices, although the concentrations in the placenta and umbilical cord were more suitable for predicting neonatal outcomes. Buprenorphine concentrations were lower and required sensitive instrumentation, as measuring buprenorphine glucuronidated metabolites is critical to predict neonatal outcomes. CONCLUSIONS: Unconventional matrices are good alternatives to conventional ones for monitoring drug exposure during pregnancy. However, data are currently scarce on buprenorphine and methadone during pregnancy to accurately interpret their concentrations. Clinical studies should be conducted with larger cohorts, considering confounding factors such as illicit drug co-exposure.