Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial.

BACKGROUND: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response. METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics. RESULTS: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%. CONCLUSIONS: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.

Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine.

BACKGROUND: Oliceridine (Olinvyk) is a µ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. METHODS: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm. RESULTS: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway. CONCLUSIONS: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

A Randomized Trial Assessing the Safety, Pharmacokinetics, and Efficacy During Morning Off of AZ-009.

BACKGROUND: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). OBJECTIVE: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD. METHODS: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose. RESULTS: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg). CONCLUSIONS: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management.

AIM: Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants. METHODS: This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h-1 of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h-1 ) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated. RESULTS: No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of Cmax and AUCinf with an estimated t1/2 of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent. CONCLUSION: STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h-1 . Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed. TRIAL REGISTRY: EudraCT (2014-002402-21) and toetsingonline.nl (63085).

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.

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.