Oliceridine, a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model

Fossler, Michael J.; Sadler, Brian M.; Farrell, Colm; Burt, David; Pitsiu, Maria; Skobieranda, Franck; Soergel, David G.

doi:10.1002/jcph.1075

Cited by 8 publications

(6 citation statements)

References 10 publications

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“…In fact, quite a number of simulations supporting further clinical development of oliceridine have been performed to guide the clinical development of oliceridine and are detailed elsewhere. 16 A serial 3-compartment model with first-order and saturable clearance terms was used to describe the time course of oliceridine concentrations in plasma after intravenous administration. Mammillary and 2compartment models were evaluated but did not perform as well in describing the observed concentration data.…”

Section: Discussionmentioning

confidence: 99%

“…15 The objective of the present analysis was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the PK and PD of oliceridine, using all the available phase 1 and phase 2 data. This article describes the development and qualification of the model; the related article 16 will describe the simulations performed in support of further clinical development of oliceridine.…”

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confidence: 99%

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Oliceridine (TRV130), a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model

Fossler¹,

Sadler

Farrell

et al. 2018

The Journal of Clinical Pharma

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Conventional opioids bind to μ-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and β-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the μ-opioid receptor that differentially activates G-protein coupling while mitigating β-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score. Phase 1 data consisted of 145 subjects (88% male, 12% female), who received single doses of oliceridine ranging between 0.15 and 7 mg, as well as multiple doses ranging from 0.4 to 4.5 mg every 4-6 hours. Sixteen of these subjects were CYP2D6 poor metabolizers, who have lower oliceridine clearance than extensive metabolizers. Approximately 265 subjects (10% male, 90% female) came from the phase 2 study, in which they received active doses ranging from 0.5 to 4 mg every 3-4 hours. The final model was a 3-compartment model that included covariates of body weight, sex, and CYP2D6 status. The PD model was an indirect response model linked to plasma oliceridine concentrations and included the placebo pain response over the 48-hour treatment period. The EC for oliceridine on pain relief was estimated as 10.1 ng/mL (95%CI, 8.4-12.1 ng/mL). Model qualification showed that the model robustly reproduced the original data.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oliceridine (TRV130), a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model

Fossler¹,

Sadler

Farrell

et al. 2018

The Journal of Clinical Pharma

Self Cite

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“…22 The mean steadystate volume of distribution of oliceridine ranges from 90 to 120 L. Oliceridine is metabo lized primarily by cytochrome P450 (CYP)3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19. 11,23 The metabolites have no obvious activity to the µopioid receptor. The halflife of oliceridine is 1.3 to 3 hours.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Oliceridine for the Management of Acute Postoperative Pain

Liu

Yang

2021

Ann Pharmacother

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Objective To review the pharmacological characteristics, clinical evidence, and place in the management of acute postoperative pain severe enough to require an intravenous opioid. Data Sources A comprehensive literature search was conducted in PubMed (January 2000 to December 1, 2020). Key search terms included oliceridine or acute postoperative pain. Other sources were derived from product labeling and ClinicalTrials.gov. Study Selection and Data Extraction All English-language articles identified from the data sources were reviewed and evaluated. Phase I, II, and III clinical trials were included. Data Synthesis Oliceridine is a novel selective µ-receptor G-protein pathway modulator. It has the property of activating G-protein signaling while causing low β-arrestin recruitment to the µ-receptor. Intravenous oliceridine showed statistically superior analgesia than placebo in patients with moderate or severe pain after surgery, with a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects, compared with morphine. Relevance to Patient Care and Clinical Practice The analgesic capacity of oliceridine is at least comparable to that of morphine at clinically relevant dosages, with a rapid onset of action. Also, it may be associated with a lower incidence of adverse events at dosing regimens associated with comparable analgesia. These data suggest that oliceridine may provide an important new treatment option for the management of moderate to severe postoperative pain where an intravenous opioid is warranted. Conclusion Oliceridine has obvious analgesic effects in patients with moderate or severe pain after surgery; additionally, it has a favorable safety and tolerability profile.

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“…As a result, when used as sedatives, dose adjustments are not necessary, although these would have to be studied in a controlled setting if oliceridine were to be developed for a sedation indication. [ 14 ]…”

Section: Oliceridinementioning

confidence: 99%

“…Simulation studies suggest that oliceridine doses of 1–3 mg pro re nata (PRN) are probably effective in reducing numeric pain-rating scale (NPRS) scores relative to placebo. [ 14 ] If required, the supplemental doses should be 1 mg and administered about 15 min after the loading dose. These studies also suggest that when oliceridine is administered on an as-needed basis, a longer interval between doses is observed in simulated CYP2D6 poor metabolizers, consistent with their reduced oliceridine clearance.…”

Section: Oliceridinementioning

confidence: 99%

Oliceridine and its potential to revolutionize GI endoscopy sedation

Goudra

Singh

2020

Saudi J Anaesth

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Providing sedation to patients undergoing gastrointestinal (GI) endoscopy is a controversial and emotive issue. The mainstay of sedation is propofol, whose administration is within the sole jurisdiction of anesthesia providers, at least in the USA. Attempts have been made to seize the authority by the GI community. One of the first attempts was the use of the prodrug of propofol –fospropofol. However, as the drug has a similar adverse effect profile as propofol in terms of respiratory depression, the FDA did not approve its use by providers other than those trained in airway management. Sedasys ® was the next attempt, which was a computer-assisted personalized sedation system. As a result of insufficient sedation that could be provided with the device, although very successful in research settings, it was not a commercial success. It seems that remimazolam is the next effort in this direction. It is likely to fail in this regard unless its respiratory depressant properties and failure rates could be addressed. G protein-biased μ-receptor agonists are a new class of opioids exhibiting analgesic properties similar to morphine without equivalent respiratory depressant properties. Oliceridine is the prototype. As a result, the drug can be additive to midazolam or remimazolam and allow screening colonoscopy to be comfortably completed without the need for propofol. For an anesthesia provider, the administration of oliceridine can eliminate the need for drugs such as fentanyl that add to the respiratory depressant properties of propofol. As a result, oliceridine has the potential to render the sedation for GI endoscopy procedures both safe and cost-effective.

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Oliceridine, a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model

Cited by 8 publications

References 10 publications

Oliceridine (TRV130), a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model

Oliceridine (TRV130), a Novel G Protein–Biased Ligand at the μ‐Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model

Oliceridine for the Management of Acute Postoperative Pain

Oliceridine and its potential to revolutionize GI endoscopy sedation

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