Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial.

Importance: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl). Objective: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose. Design, Setting, and Participants: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023. Intervention: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference). Main Outcomes and Measures: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics. Results: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes. Conclusions and Relevance: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04764630.

Sunscreen use amongst US adults: a national survey.

One in five Americans will develop skin cancer before the age of 70. Consistent sunscreen use can help decrease the prevalence of this. This study assesses the general knowledge of United States citizens on sunscreen use, frequency of usage, common behaviors of sunscreen usage, and use of sunscreen based on knowledge of sun protection. We created a 14-question anonymous web-based survey that was distributed amongst a third-party polling service. The polling service conducted random recruitment of participants based on inclusion criteria. Results from 200 participants were then analyzed using JMP Pro 16 for the Mac [11]. Fishers two tailed exact test was used along with Wilcoxon's rank- sum test. The results of the survey found that 11% of the participants report not wearing sunscreen at all, 13.5% wear sunscreen daily, the most common reason for sunscreen use was avoidance of sunburns (50%, n = 100), most people learn about the importance of sunscreen from their parents/family members (46.5%, n = 93), and 66.5% of the participants feel that sunscreen education should be included in schools (n = 133). Furthermore, the participants in the lowest income bracket were less likely to apply sunscreen. In conclusion, our survey found that most US residents are aware about sunscreen's role in protection from UV rays, however, most citizens continue to use it inconsistently.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (III) A Randomized Trial with Interferon Beta-1a Products.

The US Food and Drug Administration (FDA) has taken steps to bring efficiency to the development of biosimilars, including establishing guidance for the use of pharmacokinetic and pharmacodynamic (PD) similarity study data without a comparative clinical study with efficacy end point(s). To better understand the potential role for PD biomarkers in biosimilar development and inform best practices for biomarker selection and analysis, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants. Eighty-four healthy participants (n = 12 per dose arm) received either placebo or one of three doses of either interferon ß-1a (7.5-30 µg) or pegylated interferon ß-1a (31.25-125 µg) to evaluate the maximum change from baseline and the baseline-adjusted area under the effect curve for the biomarkers neopterin in serum and myxovirus resistance protein 1 in blood. Both PD biomarkers increased following product administration with clear separation from baseline (neopterin: 3.4-fold and 3.9-fold increase for interferon ß-1a and pegylated interferon ß-1a, respectively; myxovirus resistance protein 1: 19.0-fold and 47.2-fold increase for interferon ß-1a and pegylated interferon ß-1a, respectively). The dose-response curves support that therapeutic doses were adequately sensitive to detect differences in both PD biomarkers for consideration in a PD similarity study design. Because baseline levels of both biomarkers are low compared with on-treatment values, there was little difference in using PD measures adjusted to baseline compared with the results without baseline adjustment. This study illustrates potential methodologies for evaluating PD biomarkers and an approach to address information gaps when limited information is publicly available for one or more PD biomarkers.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (I) A Randomized Trial with PCSK9 Inhibitors.

US Food and Drug Administration (FDA) guidance outlines how biosimilars can be developed based on pharmacokinetic (PK) and pharmacodynamic (PD) similarity study data in lieu of a comparative clinical efficacy study. There is a paucity of PD comparability studies in biosimilar development, leaving open questions about how best to plan these studies. To that end, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants to evaluate approaches to address information gaps, inform analysis best practices, and apply emerging technologies in biomarker characterization. Seventy-two healthy participants (n = 8 per arm) received either placebo or one of four doses of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab (15-100 mg) or evolocumab (21-140 mg) to evaluate the maximum change from baseline (ΔPDmax ) and the baseline-adjusted area under the effect curve (AUEC) for the biomarkers low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in serum. We investigated approaches to minimize variability in PD measures. Coefficient of variation was lower for LDL-C than apoB at therapeutic doses. Modeling and simulation were used to establish the dose-response relationship and provided support that therapeutic doses for these products are adequately sensitive and are on the steep part of the dose-response curves. Similar dose-response relationships were observed for both biomarkers. ΔPDmax plateaued at lower doses than AUEC. In summary, this study illustrates how pilot study data can be leveraged to inform appropriate dosing and data analyses for a PK and PD similarity study.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (II) A Randomized Trial with IL-5 Antagonists.

The US Food and Drug Administration (FDA) guidance describes how pharmacodynamic (PD) biomarkers can be used to address residual uncertainty and demonstrate no clinically meaningful differences between a proposed biosimilar and its reference product without relying on clinical efficacy end point(s). Pilot studies and modeling can inform dosing for such PD studies. To that end, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants to evaluate approaches to address information gaps, inform best practices for analysis of biomarker samples and study results, and apply emerging technologies in biomarker characterization. Seventy-two healthy participants (n = 8 per arm) received either placebo or 1 of 4 doses of the interleukin-5 inhibitors mepolizumab (3-24 mg) or reslizumab (0.1-0.8 mg/kg). A clinical study using doses lower than approved therapeutic doses was combined with modeling and simulation to evaluate the dose-response relationship of the biomarker eosinophils. There was no dose-response relationship for eosinophil counts due to variability, although the mepolizumab 24 mg and reslizumab 0.8 mg/kg doses showed clear effects. Published indirect-response models were used to explore eosinophil data across doses from this study and the unstudied therapeutic doses. Simulations were used to calculate typical PD metrics, such as baseline-adjusted area under the effect curve and maximum change from baseline. The simulation results demonstrate sensitivity of eosinophils as a PD biomarker and indicate doses lower than the approved doses would have PD responses overlapping with variability in the placebo arm. The simulation results further highlight the utility of model-based approaches in supporting use of PD biomarkers in biosimilar development.

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial.

Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.

Bullous Pemphigoid Complicated by Sepsis.

Patients with bullous pemphigoid face many challenges when managing their disorder, one of which is balancing medication with their ailments. Because the patient population with bullous pemphigoid are primarily elderly, the current first-line treatment of corticosteroids tends to increase their rates of morbidity and mortality. During the acute process of the disease, providers must also consider the increased chance of infections caused by the opening in the skin. These patient cases are often complicated further by secondary symptoms such as pruritis and pain. Here we present a case in which we provided care to a 38-year-old female with a history of bullous pemphigoid and multiple medical problems who presented to the emergency department with nausea, vomiting, fevers, abdominal pain, and blisters on her forearm. Due to concern for sepsis and her past failure of outpatient therapy, the patient was hospitalized and treated for her possible infection, bullous pemphigoid, nausea, and pain.

An ominous cause of back pain: Vertebral Osteomyelitis.

The authors present the case of a patient seen for back pain in the emergency department, initially discharged home with a diagnosis of musculoskeletal pain. He returned a week later and was found to have vertebral osteomyelitis based on a thorough neurologic exam. A review of ominous causes of back pain, including the elusive nature of vertebral osteomyelitis/diskitis is discussed.

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.