Benefit and risk evaluation of biased mu-receptor agonist oliceridine versus morphine

Background: To improve understanding of the respiratory behavior of oliceridine, a mu-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the beta-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility.Methods: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers ( n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia >= 0.5) - P(respiratory depression >= 0.25), where analgesia >= 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression >= 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median +/- standard error of the estimate.Results: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 +/- 4.9 ng/ml; morphine 34.3 +/- 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 +/- 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 +/- 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia.Conclusions: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range

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. © 2013 American Association of Pharmaceutical Scientists