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

Abstract

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.

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

“…The pharmacokinetic/pharmacodynamic (PK/PD) model used for all simulations has been reported previously . The PK model was a serial 3‐compartment model with both linear and saturable clearance pathways.…”

“…The pharmacokinetic/pharmacodynamic (PK/PD) model used for all simulations has been reported previously. 6 The PK model was a serial 3-compartment model with both linear and saturable clearance pathways. Because oliceridine is metabolized by both CYP3A and CYP2D6, 5 CYP2D6 metabolizer status was included as a covariate in the model.…”

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

“…So far, this is the only molecule from G protein-biased opioids family, tested in clinical trials [59][60][61][62][63]. It was recently approved by the U.S. Food and Drug Administration for the management of moderate to severe acute pain in adults [64].…”

Therapeutic Potential of Targeting ß-Arrestin

“…These and other findings led to the development of TRV130, also known as oliceridine, a Gi/o-biased ligand (DeWire et al., 2013; Altarifi et al., 2017) for the μOR. Clinical trials using TRV130 for phase II (Viscusi et al., 2016; Singla et al., 2017) and III studies (APOLLO-1 and -2) have been completed, and while the results are not yet published, TRV-130 displayed greater analgesia and less gastrointestinal and respiratory side effects compared to morphine (Fossler et al., 2018). Currently, an open-label safety study is underway (ATHENA trial).…”