Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder.

BACKGROUND: BUP-XR (SUBLOCADE®) is the first buprenorphine extended-release subcutaneous injection approved in the USA for monthly treatment of moderate-to-severe opioid use disorder (OUD). Among patients with OUD, those who inject or use high doses of opioids likely require higher doses of buprenorphine to maximize treatment efficacy. The objective of this analysis was to compare the efficacy and safety of 100-mg versus 300-mg maintenance doses of BUP-XR in OUD patients who inject opioids. METHODS: This was a secondary analysis of a randomized, double-blind, placebo-controlled study in which adults with moderate or severe OUD received monthly injections of BUP-XR (2 × 300-mg doses, then 4 × 100-mg or 300-mg maintenance doses) or placebo for 24 weeks. Abstinence was defined as opioid-negative urine drug screens combined with negative self-reports collected weekly. Each participant's percentage abstinence was calculated after the first, second, and third maintenance doses in opioid-injecting and non-injecting participants. The proportion of participants achieving opioid abstinence in each group was also calculated weekly. Treatment retention rate following the first maintenance dose was estimated for opioid-injecting participants with Kaplan-Meier method. Risk-adjusted comparisons were made via inverse propensity weighting using propensity scores. Buprenorphine plasma concentration-time profiles were compared between injecting and non-injecting participants. The percentages of participants reporting treatment-emergent adverse events were compared between maintenance dose groups within injecting and non-injecting participants separately. RESULTS: BUP-XR 100-mg and 300-mg maintenance doses were equally effective in non-injecting participants. However, in opioid-injecting participants, the 300-mg maintenance dose delivered clinically meaningful improvements over the 100-mg maintenance dose for treatment retention and opioid abstinence. Exposure-response analyses confirmed that injecting participants would require higher buprenorphine plasma concentrations compared to non-injecting opioid participants to achieve similar efficacy in terms of opioid abstinence. Importantly, both 100- and 300-mg maintenance doses had comparable safety profiles, including hepatic safety events. CONCLUSIONS: These analyses show clear benefits of the 300-mg maintenance dose in injecting participants, while no additional benefit was observed in non-injecting participants relative to the 100-mg maintenance dose. This is an important finding as opioid-injecting participants represent a high-risk and difficult-to-treat population. Optimal buprenorphine dosing in this population might facilitate harm reduction by improving abstinence and treatment retention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02357901.

A Delta-Opioid Receptor Gene Polymorphism Moderates the Therapeutic Response to Extended-Release Buprenorphine in Opioid Use Disorder.

BACKGROUND: Buprenorphine treatment is not equally effective in all patients with opioid use disorder (OUD). Two retrospective studies showed that, among African Americans (AAs), rs678849, a polymorphism in the delta-opioid receptor gene, moderated the therapeutic effect of sublingual buprenorphine. METHODS: We examined rs678849 as a moderator of the response to an extended-release subcutaneous buprenorphine formulation (BUP-XR) in a 24-week OUD treatment study of 127 AAs and 327 European Americans (EAs). Participants were randomly assigned to receive: (1) BUP-XR as 2 monthly injections of 300 mg followed by either 300 mg monthly or 100 mg monthly for 4 months, or (2) monthly volume-matched placebo injections. Generalized estimating equations logistic regression analyses tested, per population group, the main and interaction effects of treatment (BUP-XR vs placebo) and genotype group (rs678849*CC vs CT/TT) on weekly urine drug screens (UDS). RESULTS: Among AAs, the placebo group had higher rates of opioid-positive UDS than the BUP-XR group (log odds ratio = 1.67, 95% CI = 0.36, 2.98), but no genotype by treatment effect (P = .80). Among EAs, the placebo group also showed higher rates of opioid-positive UDS than the BUP-XR group (log odds ratio = 1.97, 95% CI = 1.14, 2.79) but a significant genotype by treatment interaction (χ 2(1) = 4.33, P = .04). CONCLUSION: We found a moderating effect of rs678849 on the response to buprenorphine treatment of OUD in EAs, but not AAs. These findings require replication in well-powered, prospective studies of both AA and EA OUD patients treated with BUP-XR and stratified on rs678849 genotype.

Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18-65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901. FINDINGS: From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p<0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting. INTERPRETATION: Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products. FUNDING: Indivior.

Exposure-response analysis after subcutaneous administration of RBP-7000, a once-a-month long-acting Atrigel formulation of risperidone.

AIMS: A new, long-acting, subcutaneous (SC) formulation of risperidone (RBP-7000) has been developed for the treatment of schizophrenia to address issues of non-adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure-response relationship between total active moiety (AM) plasma exposure (risperidone + 9-hydroxy-risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impression severity (CGI-S) scores using data from a registration trial. METHODS: This was a Phase 3 randomized, double-blind, placebo-controlled, multicenter study in 354 patients to evaluate the efficacy, safety and tolerability of RBP-7000 (90 mg and 120 mg). Non-linear mixed effects modelling was used to develop an integrated population pharmacokinetic/pharmacodynamic (PK/PD) model that included a joint PK model for risperidone and 9-hydroxy-risperidone with placebo and drug-effect models to establish the relation between total AM exposure and PANSS or CGI-S scores. RESULTS: CYP2D6 poor and intermediate metabolizers had lower formation rates of 9-hydroxy-risperidone (94% and 76% lower, respectively) compared to the extensive CYP2D6 metabolizers. The maximum placebo-corrected relative decrease in PANSS score from baseline following RBP-7000 treatment was 5.4%, half of which could be achieved at plasma concentrations of 4.6 ng ml-1 of the total AM. A proportional odds model for the CGI-S score related the total AM plasma concentration to the probability of improving/worsening scores over time. CONCLUSIONS: Exposure-response analysis was established between total AM concentrations and PANSS and CGI-S scores, with good precision in parameter estimates. CYP2D6 phenotype on risperidone metabolism was the only identified covariate.

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection.

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic-pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration-time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin's indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK-PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .

Model-based approach to early predict prolonged high grade neutropenia in carboplatin-treated patients and guide G-CSF prophylactic treatment.

PURPOSE: Neutropenia is a major dose-limiting side effect of chemotherapy and is closely related to febrile neutropenia which mainly occurs during the first cycle. Our objectives were to establish model-based decision rules from early absolute neutrophil counts (ANC) to anticipate prolonged high grade neutropenia at cycle 1 and to prevent it through delayed granulocyte colony stimulating factor (G-CSF) administration in carboplatin-treated patients. METHODS: The decision rules were built from Monte Carlo simulations performed with a previously published semi-mechanistic model describing ANC time-course in carboplatin-treated patients with or without concomitant G-CSF therapy. RESULTS: ANC measured at day 0 (D0, baseline), D4 and D5 were good predictors of prolonged high grade neutropenia at cycle 1. Pegfilgrastim administration on D5 was as effective as the conventional pegfilgrastim administration on D1 but none avoided prolonged high grade neutropenia in all patients. Additional decision rules were thus derived, using the same ANC combination, to identify patients for whom G-CSF was beneficial. All decision rules showed good performances (sensitivity/specificity). CONCLUSION: We propose an innovative approach to guide oncologist in their clinical practice. The next step is to perform prospective studies to implement, validate and possibly refine the proposed decision rules.

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest.

Introduction: Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the µ-opioid receptor antagonists naloxone and nalmefene. Methods: This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment. Results: Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene. Conclusion: Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

An Open-Label Study to Assess Monthly Risperidone Injections (180 mg) Following Switch from Daily Oral Risperidone (6 mg) in Stable Schizophrenic Patients.

BACKGROUND AND OBJECTIVE: Long-acting injectable antipsychotics have shown benefits over oral medications with reduced hospitalization rates and improved health-related quality of life. RBP-7000 (PERSERIS®) is a monthly risperidone formulation (90 or 120 mg) for the treatment of schizophrenia administered by subcutaneous abdominal injection. The objective of this study was to assess a higher dose of 180 mg RBP-7000 and an alternate injection site. METHODS: Following stabilization on 6 mg/day (3 mg twice daily) oral risperidone, clinically stable schizophrenic participants received 3 monthly doses of 180 mg RBP-7000 in the abdomen followed by a fourth monthly dose of 180 mg RBP-7000 in the upper arm (each dose administered as two 90-mg injections). The primary endpoint was the steady-state average plasma concentration (Cavg(ss)) of risperidone and total active moiety after oral and RBP-7000 administration. Secondary endpoints included measures of clinical efficacy (Positive and Negative Syndrome Scale, Clinical Global Impression Scale for Severity of Illness), safety, and local injection-site tolerability to assess the switch from oral risperidone and compare injection sites. RESULTS: In all, 23 participants received at least one dose of RBP-7000, 16 received all four doses, and 15 completed the study. Monthly doses of 180 mg RBP-7000 provided similar Cavg(ss) of total active moiety compared with 6 mg/day oral risperidone. The pharmacokinetics of RBP-7000 were similar after injection in the abdomen versus upper arm. Clinical efficacy measures remained stable throughout the study. All RBP-7000 injections were well tolerated with no unexpected safety findings. CONCLUSIONS: The results support the use of 180 mg RBP-7000 in schizophrenic patients stable on 6 mg/day oral risperidone and a second injection site in the upper arm. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03978832.

Model-based approach to describe G-CSF effects in carboplatin-treated cancer patients.

PURPOSE: Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects. METHODS: The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation. RESULTS: Our model well described the data in all patients. Model simulations showed that G-CSF was not as beneficial as expected in some patients. Furthermore, a longer and stronger effect was observed for the pegylated formulation in comparison with the daily standard formulation even if the latter was given for 11 consecutive days. CONCLUSIONS: The proposed model allows a mechanistic interpretation of G-CSF effects on ANC and raises the question of a systematic beneficial effect of G-CSF treatment. Other studies are needed to confirm these findings and help identifying patients for whom G-CSF is beneficial.

Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder.

The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2-3 ng/ml (corresponding to ≥70% brain mu-opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.

Modeling buprenorphine reduction of fentanyl-induced respiratory depression.

BACKGROUNDPotent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression.METHODSTo characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075-0.35 mg/70 kg (opioid naive) and 0.25-0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models.RESULTSBuprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed.CONCLUSIONOverall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine.TRIAL REGISTRATIONTrialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028)FUNDINGIndivior Inc., North Chesterfield, Virginia, USA.

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.

Optimizing ciprofloxacin dosing in intensive care unit patients through the use of population pharmacokinetic-pharmacodynamic analysis and Monte Carlo simulations.

OBJECTIVES: To explore different ciprofloxacin dosage regimens for the treatment of intensive care unit (ICU) patients with respect to clinical outcome and the development of bacterial resistance for the major Gram-negative pathogens. METHODS: A population pharmacokinetic model was first developed on ciprofloxacin serum concentrations obtained in 102 ICU patients. Then, based on this model, pharmacokinetic-pharmacodynamic Monte Carlo simulations (MCSs) were carried out to explore the appropriateness of different ciprofloxacin dosage regimens in ICU patients. The defined targets were free AUC(24)/MIC ≥90 h (as a predictor of clinical outcome) and T(MSW) ≤20% (as a predictor of selecting resistance), where T(MSW) is the time spent within the mutant selection window over 24 h. Two simulation trials were conducted: Trial 1 took into account the whole MIC distribution for each causative pathogen in line with empirical antibiotherapy; Trial 2 used MIC breakpoints given by the Antibiogram Committee of the French Microbiology Society in order to treat the 'worst-case' scenario. RESULTS: Trial 1 showed that for Pseudomonas aeruginosa and Acinetobacter baumannii, the common dosage regimens of 400 mg twice or three times a day did not achieve the desired target attainment rates (TARs) with respect to T(MSW), while suboptimal TARs were found for AUC(24)/MIC. Trial 2 showed that ≤ 18% of patients reached the target of T(MSW) ≤ 20% for MIC breakpoints of 0.5 and 1 mg/L, regardless of the administered dose. CONCLUSIONS: Based on the mutant selection window concept, our simulations truly question the use of ciprofloxacin for the treatment of P. aeruginosa and A. baumannii infections in ICU patients due to the potential for developing resistance.

A new exact test for the evaluation of population pharmacokinetic and/or pharmacodynamic models using random projections.

PURPOSE: Within-subject dependency of observations has a strong impact on the evaluation of population pharmacokinetic (PK) and/or pharmacodynamic (PD) models. To our knowledge, none of the current model evaluation tools correctly address this issue. We present a new method with a global test and easy diagnostic plot which relies on the use of a random projection technique that allows the analysis of dependent data. METHODS: For each subject, the vector of standardised residuals is calculated and projected onto many random directions drawn uniformly from the unit sphere. Our test compares the empirical distribution of projections with their distribution under the model. Simulation studies assess the level of the test and compare its performance with common metrics including normalised prediction distribution errors and different types of weighted residuals. An application to real data is performed. RESULTS: In contrast to other evaluated methods, our test shows adequate level for all models and designs investigated, which confirms its good theoretical properties. The weakness of other methods is demonstrated and discussed. CONCLUSIONS: This new test appears promising and could be used in combination with other tools to drive model evaluation in population PK/PD analyses.

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.

Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials.

BACKGROUND: BUP-XR (a.k.a. RBP-6000 or SUBLOCADE™) is an extended-release subcutaneous buprenorphine formulation for the treatment of opioid use disorder. BUP-XR was designed to provide sustained buprenorphine exposure throughout the monthly dosing interval, at concentrations sufficient to control all aspects of the disease (withdrawal, craving, and blockade of opioid subjective effects). OBJECTIVES: To characterize the population pharmacokinetics of BUP-XR based on phase II and phase III data and to evaluate whether target therapeutic concentrations were reached with the dosing regimens evaluated in the phase III program. METHODS: The population pharmacokinetic analysis included 570 subjects with opioid use disorder who received up to 12 monthly BUP-XR injections following induction with sublingual buprenorphine. RESULTS: In phase III studies, target therapeutic concentrations of buprenorphine were achieved from the first injection and maintained over the entire treatment duration. Buprenorphine plasma concentration-time profiles were well described by a two-compartment model, with first-order absorption for sublingual buprenorphine and a dual absorption submodel for BUP-XR. A covariate analysis evaluated the effects of subjects' demographic characteristics, laboratory data, and genetic status regarding buprenorphine-metabolizing enzymes. Only two covariates, body mass index and body weight, were retained in the final model. Overall, their effects were not of sufficient magnitude to justify a dose adjustment. Finally, pharmacokinetic simulations showed that buprenorphine plasma concentrations decreased slowly after discontinuation of treatment and that a 2-week occasional delay in dosing would not impact efficacy, which translated into labeling claims. DISCUSSION: In conclusion, the present analysis led to the development of a robust population pharmacokinetic model and confirms the ability of BUP-XR to deliver and maintain therapeutic plasma concentrations over the entire treatment duration.

Tolerance to Opioid-Induced Respiratory Depression in Chronic High-Dose Opioid Users: A Model-Based Comparison With Opioid-Naïve Individuals.

Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid-naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (Emax ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naïve and opioid-tolerant.

Evaluation of different tests based on observations for external model evaluation of population analyses.

To evaluate by simulation the statistical properties of normalized prediction distribution errors (NPDE), prediction discrepancies (pd), standardized prediction errors (SPE), numerical predictive check (NPC) and decorrelated NPC (NPC(dec)) for the external evaluation of a population pharmacokinetic analysis, and to illustrate the use of NPDE for the evaluation of covariate models. We assume that a model M(B) has been built using a building dataset B, and that a separate validation dataset, V is available. Our null hypothesis H(0) is that the data in V can be described by M(B). We use several methods to test this hypothesis: NPDE, pd, SPE, NPC and NPC(dec). First, we evaluated by simulation the type I error under H(0) of different tests applied to the four methods. We also propose and evaluate a single global test combining normality, mean and variance tests applied to NPDE, pd and SPE. We perform tests on NPC and NPC(dec), after a decorrelation. M(B) was a one compartment model with first order absorption (without covariate), previously developed from two phase II and one phase III studies of the antidiabetic drug, gliclazide. We simulated 500 external datasets according to the design of a phase III study. Second, we investigated the application of NPDE to covariate models. We propose two approaches: the first approach uses correlation tests or mean comparisons to test the relationship between NPDE and covariates; the second evaluates NPDE split by category for discrete covariates or quantiles for continuous covariates. We generated several validation datasets under H(0) and under alternative assumptions with a model without covariate, with one continuous covariate (weight), or one categorical covariate (sex). We calculated the powers of the different tests using simulations, where the covariates of the phase III study were used. The simulations under H(0) show a high type I error for the different tests applied to SPE and an increased type I error for pd. The different tests present a type I error close to 5% for the global test appied to NPDE. We find a type I error higher than 5% for the test applied to classical NPC but this test becomes close to 5% for NPC(dec). For covariate models, when model and validation dataset are consistent, type I error of the tests are close to 5% for both effects. When validation datasets and models are not consistent, the tests detect the correlation between NPDE and the covariate. We recommend to use NPDE over SPE for external model evaluation, since they do not depend on an approximation of the model and have good statistical properties. NPDE represent a better approach than NPC, since in order to perform tests on NPC, a decorrelation step must be applied before. NPDE, in this illustration, is also a good tool to evaluate model with or without covariates.

Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm.

Pharmacogenetics is now widely investigated and health institutions acknowledge its place in clinical pharmacokinetics. Our objective is to assess through a simulation study, the impact of design on the statistical performances of three different tests used for analysis of pharmacogenetic information with nonlinear mixed effects models: (i) an ANOVA to test the relationship between the empirical Bayes estimates of the model parameter of interest and the genetic covariate, (ii) a global Wald test to assess whether estimates for the gene effect are significant, and (iii) a likelihood ratio test (LRT) between the model with and without the genetic covariate. We use the stochastic EM algorithm (SAEM) implemented in MONOLIX 2.1 software. The simulation setting is inspired from a real pharmacokinetic study. We investigate four designs with N the number of subjects and n the number of samples per subject: (i) N = 40/n = 4, similar to the original study, (ii) N = 80/n = 2 sorted in 4 groups, a design optimized using the PFIM software, (iii) a combined design, N = 20/n = 4 plus N = 80 with only a trough concentration and (iv) N = 200/n = 4, to approach asymptotic conditions. We find that the ANOVA has a correct type I error estimate regardless of design, however the sparser design was optimized. The type I error of the Wald test and LRT are moderatly inflated in the designs far from the asymptotic (<10%). For each design, the corrected power is analogous for the three tests. Among the three designs with a total of 160 observations, the design N = 80/n = 2 optimized with PFIM provides both the lowest standard error on the effect coefficients and the best power for the Wald test and the LRT while a high shrinkage decreases the power of the ANOVA. In conclusion, a correction method should be used for model-based tests in pharmacogenetic studies with reduced sample size and/or sparse sampling and, for the same amount of samples, some designs have better power than others.

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder.

Extensive 12-lead electrocardiogram monitoring and drug concentrations were obtained during development of BUP-XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1,114 subjects were pooled from 5 studies in OUD. A concentration-QT model was developed, which accounted for confounding factors (e.g., comedications) affecting heart rate and heart rate-corrected QT interval (QTc). Bias-corrected nonparametric two-sided 90% confidence intervals (CIs) were derived for the mean predicted effect of BUP-XR on QTc (ΔQTc) at therapeutic and supratherapeutic doses. Changes in QTc were associated with age, central vs. noncentral reading, sex, methadone, and barbiturates. The upper 90% CI of ΔQTc was 0.29, 0.67, and 1.34 ms at the steady-state peak concentration (Cmax ) for 100, 300, and 2 × 300 mg doses, respectively. An effect of BUP-XR on QT can be ruled out at therapeutic and supratherapeutic doses of BUP-XR, after accounting for covariates that may influence heart rate and QT interval in OUD.