Journal of clinical pharmacology
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Randomized Controlled Trial
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.
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. ⋯ 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 EC50 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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To date, the actual relationship between antimuscarinics for overactive bladder (OAB) syndrome and the subsequent risk of a fracture remains unclear. The aim of this retrospective cohort study was to demonstrate the association between antimuscarinics for OAB and fractures using a large population-based data set. Data used in this study were taken from the Taiwan Longitudinal Health Insurance Database 2005. ⋯ Results revealed that the incidence rate of fracture per 100 person-years within the 3-year follow-up period were 3.01 (95% confidence interval [CI], 2.65-3.40) for OAB patients who received antimuscarinics and 2.77 (95%CI, 2.60-2.95) for those OAB patients who did not receive antimuscarinics. The adjusted hazard ratio (HR) for a subsequent fracture for OAB patients who received antimuscarinics was 1.11 (95%CI, 0.97-1.28) compared with those OAB patients who did not receive antimuscarinics. Consequently, we concluded that antimuscarinics for OAB was not significantly predictive of fracture.
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Oliceridine is a novel G protein-biased ligand at the μ-opioid receptor that differentially activates G protein coupling while mitigating β-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. ⋯ The simulations also revealed that a 1-mg "supplemental dose" given 0.25 hour after the loading dose would decrease NPRS scores further in almost one-third of patients. In addition, if oliceridine is administered prn, a longer interval between doses is observed in simulated PM patients, consistent with their reduced oliceridine clearance. Because this longer average dosing interval is predicted to decrease oliceridine exposure in PM patients, the need to know the patient's CYP2D6 genotype for dosing is effectively obviated.