Pharmacokinetics, pharmacodynamics and antinociceptive effects of buprenorphine following transdermal administration to horses.

OBJECTIVE: This study describes the pharmacokinetics and pharmacodynamics, including antinociceptive effects, of a transdermal buprenorphine solution in horses. It was hypothesized that transdermal application would lead to sustained blood concentrations and antinociceptive effects with fewer adverse effects compared with intravenous (IV) injection. STUDY DESIGN: Prospective nonrandomized four-part parallel experimental study. ANIMALS: A group of eight horses (three mares and five geldings) aged 6-12 years. METHODS: Horses were administered incremental doses of 15, 30 and 45 µg kg-1 of buprenorphine transdermal solution and a single IV dose of 5 µg kg-1 of buprenorphine with a 2 week washout period between treatments. Concentrations of buprenorphine were determined in plasma using liquid chromatography-tandem mass spectrometry and modeled using a nonlinear mixed effects population pharmacokinetic model to determine pharmacokinetic parameters. Pharmacodynamic effects, including changes in locomotor activity, heart rate, body temperature, gastrointestinal borborygmi, thermal and mechanical nociceptive thresholds were recorded. Mixed effects analysis of variance and post hoc comparisons were performed using a Bonferroni multiple comparison adjustment to assess differences in pharmacodynamic parameters between baseline and each time point within each dose group and between dose groups at the same time point. RESULTS: Transdermal application of buprenorphine resulted in low systemic concentrations relative to IV injection. Bioavailability after transdermal application was 11%. Thermal nociceptive thresholds were significantly (p < 0.05) increased (4.3-10.7% relative to baseline) for up to 72 hours in the IV dose group, but only sporadically in the transdermal dose groups (2.5-9.9% relative to baseline). Changes in locomotor activity, heart rate and borborygmi varied over time and with dose. CONCLUSIONS AND CLINICAL RELEVANCE: Limited thermal antinociceptive effects were observed at the transdermal doses studied likely owing to limited absorption relative to IV dosing. Future studies may be directed toward investigating antinociceptive effects of higher transdermal doses and different application sites.

Prone Positioning of Patients With Coronavirus Disease 2019 Who Are Nonintubated in Hypoxic Respiratory Distress: Single-Site Retrospective Health Records Review.

INTRODUCTION: In March and April 2020 of the coronavirus disease 2019 pandemic, site clinical practice guidelines were implemented for prone positioning of patients with suspected coronavirus disease 2019 in hypoxic respiratory distress who are awake, alert, and spontaneously breathing. The purpose of this pandemic disaster practice improvement project was to measure changes in pulse oximetry associated with prone positioning of patients with coronavirus disease 2019 infection in adult acute respiratory distress or adult respiratory distress syndrome, who are awake, alert, spontaneously breathing, and nonintubated. METHODS: A retrospective chart review of patients who were coronavirus disease 2019 positive in the emergency department from March 30, 2020 to April 30, 2020 was conducted for patients with a room air pulse oximetry <90% and a preprone position pulse oximetry ≤94% who tolerated prone positioning for at least 30 minutes. The primary outcome was the change in pulse oximetry associated with prone positioning, measured on room air, with supplemental oxygen, and approximately 30 minutes after initiating prone positioning. Median and mean differences were compared with the Wilcoxon signed-rank test and paired t-test. RESULTS: Of the 440 patients with coronavirus disease 2019, 31 met inclusion criteria. Median pulse oximetry increased as 83% (interquartile range, 75%-86%) on room air, 90% (interquartile range, 89%-93%) with supplemental oxygen, and 96% (interquartile range, 94%-98%) with prone positioning (z = -4.48, P < .001). A total of 45% (n = 14) were intubated during their hospital stay, and 26% (n = 8) of the included patients died. DISCUSSION: In patients with coronavirus disease 2019 who are awake, alert, and spontaneously breathing, an initially low pulse oximetry reading improved with prone positioning. Future studies are needed to determine the association of prone positioning with subsequent endotracheal intubation and mortality.

Drug Dosing Recommendations for All Patients: A Roadmap for Change.

Most drug labels do not contain dosing recommendations for a significant portion of real-world patients for whom the drug is prescribed. Current label recommendations predominately reflect the population studied in pivotal trials that typically exclude patients who are very young or old, emaciated or morbidly obese, pregnant, or have multiple characteristics likely to influence dosing. As a result, physicians may need to guess the correct dose and regimen for these patients. It is now feasible to provide dose and regimen recommendations for these patients by integrating available scientific knowledge and by utilizing or modifying current regulatory agency-industry practices. The purpose of this commentary is to explore several factors that should be considered in creating a process that will provide more effective, safe, and timely drug dosing recommendations for most, if not all, patients. These factors include the availability of real-world data, development of predictive models, experience with the US Food and Drug Administration (FDA)'s pediatric exclusivity program, development of clinical decision software, funding mechanisms like the Prescription Drug Users Fee Act (PDUFA), and harmonization of global regulatory policies. From an examination of these factors, we recommend a relatively simple, efficient expansion of current practices designed to predict, confirm, and continuously improve drug dosing for more patients. We believe implementing these recommendations will benefit patients, payers, industry, and regulatory agencies.