A population pharmacodynamic Markov mixed-effects model for determining remimazolam-induced sedation when co-administered with fentanyl in procedural sedation.

The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the Modified Observer's Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (Emax ) model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with body mass index greater than 25 kg/m2 had ~30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 µg. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 µg is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.

The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19.

Caly et al.1 reported that ivermectin inhibited severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in vitro for up to 48 hours using ivermectin at 5 µM. The concentration resulting in 50% inhibition (IC50 ; 2 µM) was > 35× higher than the maximum plasma concentration (Cmax ) after oral administration of the approved dose of ivermectin when given fasted. Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 µg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose. Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50 , even for a dose level 10× higher than the approved dose. Even with the high lung:plasma ratio, ivermectin is unlikely to reach the IC50 in the lungs after single oral administration of the approved dose (predicted lung: 0.0873 µM) or at doses 10× higher that the approved dose administered orally (predicted lung: 0.820 µM). In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Repurposing drugs for use in coronavirus disease 2019 (COVID-19) treatment is an ideal strategy but is only feasible when product safety has been established and experiments of repurposed drugs are conducted at clinically relevant concentrations.

Time-to-Event Modeling for Remimazolam for the Indication of Induction and Maintenance of General Anesthesia.

Remimazolam is an ultra-short-acting benzodiazepine being investigated for induction and maintenance of general anesthesia and for procedural sedation. This dose-response analysis of 4 phase 2-3 studies evaluated covariates that may impact the pharmacodynamic profile (based on theoretical pharmacokinetic principles) and require dose adjustments in subpopulations, particularly elderly, and if remimazolam has cumulative properties. Covariates affecting the time to loss of consciousness and time to extubation were evaluated using Cox proportional hazards models. Factors affecting steady-state infusion rate required to produce adequate sedation were evaluated using linear regression. Variability in time to loss of consciousness was explained by induction dose, age, body mass index, and time from initiation of opioids to initiation of remimazolam. The steady-state infusion rate producing adequate sedation was higher in European than Japanese subjects due to differences in study design. American Society of Anesthesiologists physical status class 3 subjects had a 28% lower maintenance infusion rate than class 1 subjects. Other statistically significant covariates (American Society of Anesthesiologists class 2, estimated glomerular filtration rate, and sex) resulted in small (≤14%), non-clinically relevant differences. Factors affecting time to extubation included the last infusion rate (ie, tapering), the bispectral index score at the end of infusion, and sex. The time to extubation after remimazolam did not increase with increased cumulative dose of remimazolam or duration of surgery. This evaluation of remimazolam's pharmacodynamic profile, in the absence of pharmacokinetic data, informed dosing recommendations and showed that remimazolam does not have cumulative properties in the general anesthesia setting.

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.

Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers.

BACKGROUND: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. METHODS: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. RESULTS: A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. CONCLUSIONS: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

Pharmacometrics-guided drug development of antihyperhidrosis agents.

The objective of the present work was to use modeling and simulation to inform trial design of a proof-of-concept study for agents used in the treatment of hyperhidrosis. Data were available from 36 subjects who received the vehicle, 2% or 4% topical glycopyrrolate wipes daily for 4 weeks, with response (hyperhidrosis disease severity scale [HDSS] and sweat production [SP]) measured weekly. The HDSS and SP time courses were best described using a longitudinal model with maximum response achieved by 1 week. Glycopyrrolate 4% had a higher HDSS responder rate than 2% (50% vs 33%) and placebo (0%) at week 1. Mean change from baseline (mg/5 min [SD]) in SP at week 1 was -90 (220), -185 (214), and -271 (265) for placebo, 2%, and 4% glycopyrrolate, respectively. Subjects with higher baseline SP had higher sweat reduction from baseline. Virtual clinical trials were simulated and analyzed using conventional (at the end of the study) versus model-based methods to determine sample size for achieving 80% power to identify a dose-response relationship. Twenty-seven subjects compared with at least 120 subjects would be needed using model-based and conventional methods, respectively. Thus, the model-based method using longitudinal data required fewer subjects than the conventional single-point method.

The effects of a short course of antibiotics on alvimopan and metabolite pharmacokinetics.

Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan C(max) by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.

In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography.

BACKGROUND: Converging lines of evidence are consistent with an inhibitory effect of the antidepressant and smoking-cessation aid bupropion on dopamine and norepinephrine reuptake, but the in vivo effects of the drug at the human dopamine transporter (DAT) have not been studied to date. This study employed positron emission tomography (PET) to assess the extent and duration of DAT receptor occupancy by bupropion and its metabolites under conditions of steady-state oral dosing with bupropion sustained-release (SR) in healthy volunteers. METHODS: Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as 3, 12, and 24 hours after the last dose of bupropion SR on day 11. RESULTS: Bupropion and its metabolites inhibited striatal uptake of the selective DAT-binding radioligand (11)C-betaCIT-FE in vivo. Three hours after the last dose of bupropion SR, average DAT occupancy by bupropion and its metabolites was 26%-a level that was maintained through the last PET assessment at 24 hours after dosing. CONCLUSIONS: Bupropion and its metabolites induced a low occupancy of the striatal DAT over 24 hours under conditions of steady-state oral dosing with therapeutic doses of bupropion SR. These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible in part for the therapeutic effects of the drug.

Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation.

Sustained-release bupropion (bupropion SR) is a unique, non-nicotine smoking cessation aid that is hypothesised to act upon neurological pathways involved in nicotine dependence. Pharmacokinetic and metabolism studies reveal that bupropion SR is metabolised by multiple pathways with no single pathway predominating. When one pathway is inhibited, others are available to compensate. Therefore, only a few clinically relevant drug-drug interactions involving bupropion SR have been observed, although the potential for interactions exists, as with any extensively metabolised drug. Population pharmacokinetic/pharmacodynamic analyses of data from patients receiving daily oral doses of 100mg, 150mg, or 300mg reveal that the anti-smoking efficacy of bupropion SR is directly related to dose. The incidences of dry mouth and insomnia were directly related to bupropion plasma concentrations while the incidence of anxiety was inversely proportional to bupropion plasma concentrations. To maximise efficacy (with an acceptable safety profile), the optimal daily dose for the majority of patients is 300mg.