Development and Verification of a Full Physiologically Based Pharmacokinetic Model for Sublingual Buprenorphine in Healthy Adult Volunteers that Accounts for Nonlinear Bioavailability.

Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome. The study aimed to develop a full physiologically based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e., untransformed or log transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. SIGNIFICANCE STATEMENT: The physiologically based pharmacokinetic (PBPK) model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for maternal-fetal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome.

Pharmacokinetics, Fecal Output, and Grimace Scores in Rabbits Given Long-acting Buprenorphine or Fentanyl for Postsurgical Analgesia.

The New Zealand white rabbit (Oryctolagus cuniculus) is a frequently used surgical model. Pain management after surgery is a critical aspect of animal welfare. Recently, a long-acting buprenorphine formulation (Ethiqa XR; EXR) was approved for use in rats and mice but has not yet been investigated in rabbits. The current study aimed to determine whether a single subcutaneous dose of 0.15mg/kg of EXR could achieve and maintain therapeutic buprenorphine plasma concentrations (0.1ng/mL) for 72h in male and female rabbits. We also evaluated the safety profiles of EXR and the fentanyl patch (FP) by assessing fecal output after surgery, because opioids are known to decrease intestinal motility. Behavior and pain scores were compared for rabbits that received either EXR or the FP after undergoing an annulus puncture procedure to induce osteoarthritis. EXR at 0.15mg/kg SC provided a shorter time to onset and sustained analgesia for 72h in male and female rabbits, whereas the FP provided suboptimal analgesia after 48h. Both EXR and FP reduced fecal output after surgery. Output returned to baseline levels within 72h for the EXR group and remained slightly below baseline at 96h after surgery for the fentanyl group. Grimace pain scores revealed no significant difference between treatment groups. These results suggest that EXR is a safe and effective option for postoperative pain management in rabbits.

Salivary Therapeutic Monitoring of Buprenorphine in Neonates After Maternal Sublingual Dosing Guided by Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Opioid use disorder (OUD) during pregnancy is associated with high mortality rates and neonatal opioid withdrawal syndrome (NOWS). Buprenorphine, an opioid, is used to treat OUD and NOWS. Buprenorphine active metabolite (norbuprenorphine) can cross the placenta and cause neonatal respiratory depression (EC 50 = 35 ng/mL) at high brain extracellular fluid (bECF) levels. Neonatal therapeutic drug monitoring using saliva decreases the likelihood of distress and infections associated with frequent blood sampling. METHODS: An adult physiologically based pharmacokinetic model for buprenorphine and norbuprenorphine after intravenous and sublingual administration was constructed, vetted, and scaled to newborn and pregnant populations. The pregnancy model predicted that buprenorphine and norbuprenorphine doses would be transplacentally transferred to the newborns. The newborn physiologically based pharmacokinetic model was used to estimate the buprenorphine and norbuprenorphine levels in newborn plasma, bECF, and saliva after these doses. RESULTS: After maternal sublingual administration of buprenorphine (4 mg/d), the estimated plasma concentrations of buprenorphine and norbuprenorphine in newborns exceeded the toxicity thresholds for 8 and 24 hours, respectively. However, the norbuprenorphine bECF levels were lower than the respiratory depression threshold. Furthermore, the salivary buprenorphine threshold levels in newborns for buprenorphine analgesia, norbuprenorphine analgesia, and norbuprenorphine hypoventilation were observed to be 22, 2, and 162 ng/mL. CONCLUSIONS: Using neonatal saliva for buprenorphine therapeutic drug monitoring can facilitate newborn safety during the maternal treatment of OUD using sublingual buprenorphine. Nevertheless, the suitability of using adult values of respiratory depression EC 50 for newborns must be confirmed.

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.

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.

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.

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.