Budget impact and pharmacy costs with targeted use of oliceridine for postsurgical pain in patients at high risk of opioid-related adverse events.

BACKGROUND: Oliceridine, a new class of µ-opioid receptor agonist, may be associated with fewer opioid-related adverse events (ORAEs) due to its unique mechanism of action. Thus, it may provide a cost-effective alternative to conventional opioids such as morphine. PATIENTS AND METHODS: Using a decision tree with a 24-hour time horizon, we calculated costs for medication and management of the three most common AEs (oxygen saturation <90%, vomiting, somnolence) following postoperative oliceridine or morphine in high-risk patients. Costs were enumerated as differences in cost of analgesics and resource utilization in the first 24 hours post-surgery. An economic model compared expected AEs and costs in a blended cohort where elderly/obese patients at higher risk for ORAEs received oliceridine while those presumed to be at lower risk received morphine with a cohort that received morphine alone. RESULTS: In high-risk patients, use of oliceridine resulted in overall savings of $363,944 (in 1,000 patients). Implementing a targeted approach of oliceridine utilization in patients with high risk for ORAEs can save a typical hospital system $122,296 in total cost of care. CONCLUSION: Use of oliceridine in postoperative care among patients at high risk provides a favorable health economic benefit compared to the use of morphine.

Oliceridine, a new class of opioid analgesics, administered directly into a vein, is a unique medication in that it provides pain relief equivalent to morphine and may have less costly side effects. It is given in a hospital/clinic or surgery center for the treatment of postoperative pain and can reduce costs compared to other opioid analgesics, possibly due to less side effects. An economic model was developed that compares morphine to oliceridine in patients more likely to experience sides effects due to traditional pain medications, comparing common side effects and pain relief following surgery. Although oliceridine costs more than morphine, in our economic model, the use of oliceridine resulted in cost savings ($363,944 US 2020 Dollars in 1,000 patients), and a positive return of investment of over 7 times, when compared to morphine.

Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk.

BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

Cost-effectiveness and cost-benefit analysis of oliceridine in the treatment of acute pain.

Aim: Oliceridine, a new class of µ-opioid receptor agonist, is selective for G-protein signaling (analgesia) with limited recruitment of ß-arrestin (associated with adverse outcomes) and may provide a cost-effective alternative versus conventional opioid morphine for postoperative pain. Patients & methods: Using a decision tree with a 24-h time horizon, we calculated costs for medication and management of three most common adverse events (AEs; oxygen saturation <90%, vomiting and somnolence) following postoperative oliceridine or morphine use. Results: Using oliceridine, the cost for managing AEs was US$528,424 versus $852,429 for morphine, with a net cost savings of $324,005. Conclusion: Oliceridine has a favorable overall impact on the total cost of postoperative care compared with the use of the conventional opioid morphine.

Lay abstract Oliceridine, a new class of opioid pain medication, given in a vein, is a unique medication in that it provides pain relief comparable to morphine and may have less costly side effects. It is given in a hospital or surgery center for the treatment of postoperative pain and can save money compared with other opioid pain medicines due to fewer side effects. An economic model was developed to compare morphine to oliceridine for common side effects and pain relief following surgery. Oliceridine use resulted in a cost saving (US$324,005; 2020 US dollars) when compared with morphine.

Assessment of Demographic and Socio-Behavioral Factors on Adherence to HIV Pre-Exposure Prophylaxis Using a Markov Modeling Approach.

Purpose: Adherence is important for the effectiveness of human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). The objective of the current work is to assess the impact of multiple demographic and socio-behavioral factors on the adherence to tenofovir-based PrEP among HIV serodiscordant couples in East Africa using Markov mixed-effects modeling approach. Methods: The Partners Demonstration Project was a prospective, open-label, implementation science-driven study of HIV PrEP among heterosexual HIV serodiscordant couples in Kenya and Uganda. The uninfected partner received oral PrEP according to the "bridge to antiretroviral therapy [ART]" strategy (i.e., until the infected partner had been on ART for ≥6 months). Adherence was monitored electronically; demographic and socio-behavioral data were collected during study visits. Analyzed data reflect 12 months of follow-up per participant. A two-state, first-order, discrete time Markov model was developed with longitudinal adherence data characterized by "dose taking (1)" and "dose missing (0)." Covariate effects were linearly added in the logit domain of transition probability parameters (P01 and P10) in the model. The full covariate model was initially developed, followed by backward elimination process to reduce the model. All significant covariates reported by a prior primary statistical analysis of the same data were included in the full covariate model. Results: The model included data from 920 participants, who were predominantly male (65%). Significant covariates associated with higher adherence were 25 years or older [odds ratio (OR) for P10, 0.61], female sex (OR for P10, 0.67), participant wanting the relationship with the partner to succeed (OR for P10, 0.79; OR for P01, 1.45), and sex with partner either with 100% or <100% condom use compared to those reported no sex (OR for P10, 0.84; OR for P01, 1.21). Significant covariates associated with lower adherence were partner on ART >6 months (OR for P01, 0.86; OR for P10, 1.34), subject in the study for >6 months (OR for P01, 0.8; OR for P10, 1.25), and problematic alcohol use (OR for P01, 0.63; OR for P10, 1.16). Conclusion: The developed Markov model provides a mechanistic understanding of relationship between demographic, socio-behavioral covariates, and PrEP adherence, by indicating the pattern of adherence influenced by each factor over time. Such data can be used for further intervention development to promote PrEP adherence.

Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed-effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used. This study included once-daily dosing regimens of placebo, oral tenofovir disoproxil fumarate (TDF), and TDF in combination with emtricitabine (FTC), administered to HIV-uninfected members of serodiscordant couples. One-coin and first- to third-order Markov models were fit to the data using NONMEM® 7.2. Model selection criteria included objective function value (OFV), Akaike information criterion (AIC), visual predictive checks, and posterior predictive checks. Covariates were included based on forward addition (α = 0.05) and backward elimination (α = 0.001). Markov models better described the data than 1-coin models. A third-order Markov model gave the lowest OFV and AIC, but the simpler first-order model was used for covariate model building because no additional benefit on prediction of target measures was observed for higher-order models. Female sex and older age had a positive impact on adherence, whereas Sundays, sexual abstinence, and sex with a partner other than the study partner had a negative impact on adherence. Our findings suggest adherence interventions should consider the role of these factors.

A report from the pediatric formulations task force: perspectives on the state of child-friendly oral dosage forms.

Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

Globalization of quantitative pharmacology: first international symposium of quantitative pharmacology in drug development and regulation.

The First International Symposium on Quantitative Pharmacology in Drug Development and Regulatory Sciences was held this past October in Nanjing, China, marking the first time scientists from around the globe gathered to discuss topics related to quantitative pharmacology in the Far East. With the recent trend toward global drug development and clinical trials in nontraditional countries, China has been regarded by many as the next frontier for the pharmaceutical industry. Quantitative pharmacology embraces all phases of pharmaceutical research and development, providing a mechanism to bridge decision making from one phase of development to the next, and it facilitates multidisciplinary partnerships through the assembly of both data and models that describe complex biological, biopharmaceutic, and clinical settings. Efforts in China are at an early stage, but it is clear that Chinese scientists embrace the discipline and are keen to promote this methodology in the registration of new drugs in China. While challenges exist, they represent an exciting area of future collaboration.