Population pharmacokinetics and pharmacodynamics of nasal glucagon in patients with type 1 or 2 diabetes.

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of glucagon after injectable or nasal administration and confirm the appropriate therapeutic dose of nasal glucagon (NG) for adult patients. Six clinical studies with PK and five clinical studies with PD (glucose) data were included in the analysis. Doses ranging from 0.5 to 6 mg NG, and 0.5 to 1 mg injectable glucagon were studied. A total of 6284 glucagon and 7130 glucose concentrations from 265 individuals (patients and healthy participants) were available. Population PK/PD modeling was performed using NONMEM. Glucagon exposure and glucose response were simulated for patients administered various doses of NG to confirm the optimal dose. Glucagon PK was well-described with a single compartment disposition with first-order absorption and elimination processes. Bioavailability of NG relative to injectable glucagon was 16%. Exposure-response modeling revealed that lower baseline glucose was associated with higher maximum drug effect. The carry-over effect from prior insulin administration was incorporated into the model through a time-dependent increase in elimination rate of glucose. Simulations showed that more than 99% of hypoglycemic adult patients would experience treatment success, defined as an increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. The population PK/PD model adequately described the PK and PD profiles of glucagon after nasal administration. Modeling and simulations confirmed that NG 3 mg is the most appropriate dose for rescue treatment during hypoglycemia emergencies.

Dose Rationale of Nasal Glucagon in Japanese Pediatric Patients with Diabetes Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation.

BACKGROUND: Nasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns. OBJECTIVE: The aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation. METHODS: We used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to < 8, 8 to < 12, and 12 to < 18 years. Treatment success was defined as an increase in blood glucose to ≥ 70 or ≥ 20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon. RESULTS: The data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that > 99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues. CONCLUSIONS: This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.

BACKGROUND: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. OBJECTIVE: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. METHODS: The effect of LY3202626 versus vehicle on amyloid-ß (Aß) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aß levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics. RESULTS: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aß1-40 and 0.228±0.244 nM for Aß1-42 in PDAPP neuronal cultures. In dogs, CSF Aß1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aß1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. CONCLUSION: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

Limiting hospital resources for acute appendicitis in children: Lessons learned from the U.S. epicenter of the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic resulted in the suspension of nonemergent surgeries throughout New York. Our tertiary care children's hospital pivoted towards a brief trial of intravenous (IV) antibiotic therapy in all patients in order to limit operating room (OR) utilization and avoid prolonged hospital stays. We describe our pandemic-based strategy for non-operative management (NOM) of appendicitis but with a limited duration of IV antibiotics. METHODS: We performed a retrospective study of children treated for acute appendicitis at our center from 3/31/2020 to 5/3/2020 during the peak of the New York pandemic. We compared appendicitis volume to similar months in prior years. We evaluated failure of NOM, length of stay, and compared characteristics of children we successfully treated with our expanded NOM protocol to previously published inclusion criteria for NOM. RESULTS: 45.5% of children (25/55) with acute appendicitis underwent NOM. Of the 30 who underwent surgery, 13 had complicated appendicitis while 17 had simple appendicitis. Three patients were COVID-positive, although none had respiratory symptoms. The majority of patients presenting with acute appendicitis (78.2%) did not meet previously published criteria for NOM. CONCLUSIONS: We treated a similar volume of children with acute appendicitis during the pandemic compared to prior years. We applied non-operative management to nearly half our patients, even as we expanded inclusion criteria for NOM to reduce OR utilization, but limited the duration of the antibiotic trial to avoid prolonged hospital stays. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: IV.

Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat.

Lanabecestat is a human ß-site amyloid precursor protein-cleaving enzyme 1 inhibitor in development to slow disease progression in patients with early Alzheimer's disease. The study evaluated the breast cancer resistance protein (BCRP) inhibition potential of lanabecestat on the pharmacokinetics (PK) of rosuvastatin, a probe for BCRP activity, in healthy white subjects who were not carriers of SLCO1B1 (c.521T>C), not homozygotes for ABCG2 (c.421C>A or c.34G>A), and not heterozygotes of ABCG2 (c.421C>A and c.34G>A). The safety of lanabecestat + rosuvastatin, the effects of rosuvastatin on the PK of lanabecestat, and the effects of multiple genetic polymorphisms on rosuvastatin exposure were assessed. Geometric mean ratios of the maximum observed rosuvastatin concentration (Cmax ), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax ) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax at steady state increased 8% in the presence of rosuvastatin. Except for an approximately 80% increase of rosuvastatin AUC (P < .05) in the heterozygotes of ABCG2 c.421C>A relative to the CC genotype, there were no statistically significant associations between rosuvastatin exposure and polymorphisms assessed. Lanabecestat + rosuvastatin was associated with few treatment-emergent adverse events, all of which resolved and were mild. Lanabecestat does not meaningfully impact BCRP activity; therefore, restriction of concomitant administration with BCRP substrates, such as rosuvastatin, may be unnecessary.

Clinically Negligible Pharmacokinetic and Pharmacodynamic Interactions Between Lanabecestat and Dabigatran Etexilate, a Prototypical P-gp Substrate.

Lanabecestat, a novel ß-site amyloid precursor protein-cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P-glycoprotein (P-gp) activity in vitro. After oral 50-mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half-maximal inhibitory concentration (IC50 ), suggesting P-gp inhibition at the intestinal wall. Plasma drug concentrations following 50 mg lanabecestat administered once daily are <10% of IC50 , suggesting minimal systemic P-gp interaction. Dabigatran etexilate (DE) is the prodrug of dabigatran, a thrombin inhibitor and P-gp substrate, making dabigatran exposure an intestinal P-gp activity indicator. This study (NCT02568397) was conducted in 60 healthy subjects receiving a single dose of 150 mg DE alone or during a lanabecestat treatment regimen. On day 16, lanabecestat and DE were coadministered; on day 20, DE was dosed 4 hours after lanabecestat. Safety was assessed using clinical labs, electrocardiogram, vital signs, Columbia Suicide Severity Rating Scale scores, adverse events, and eye and skin examinations. Pharmacokinetic/pharmacodynamic samples were collected up to 36 hours postdose. Geometric mean plasma dabigatran area under the curve from time 0 to infinity (AUC0-∞ ) and the maximum plasma drug concentration (Cmax ) increased by 15% and 17%, respectively, when coadministered with lanabecestat. When DE was dosed 4 hours after lanabecestat, there was no effect on plasma dabigatran AUC0-∞ , Cmax , or thrombin time. DE had no effect on lanabecestat's AUC0-∞ and Cmax at steady state (day 16) versus lanabecestat alone (day 15). No clinically relevant safety concerns were observed. Lanabecestat has no clinically meaningful effect on dabigatran exposure or on P-gp activity at the intestinal wall.

Population Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis of LY3015014, a Monoclonal Antibody to Protein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Healthy Subjects and Hypercholesterolemia Patients.

PURPOSE: LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles. METHODS: Single and multiple dose data from three phase1 studies in healthy subjects (n = 133), as well as a phase 2 study in hypercholesterolemia patients (n = 527) were combined into a single dataset for analysis. In this dataset, healthy subjects received single intravenous (IV) doses of 0.03 to 10 mg/kg, or multiple subcutaneous (SC) doses of 1.0 to 3.0 mg/kg, administered every 2 to 4 weeks, while patients received 20 to 300 mg every 4 weeks or 100 to 300 every 8 weeks. PK/PD analysis was performed using NONMEM (ICON, software version 7.0 level 3). PK and PD modeling were conducted sequentially, with PK parameters fixed during the development of the PK/PD model. PD parameters and estimated intersubject and intrasubject variability were obtained based on pharmacological drug exposure-response relationships. Age, baseline total PCSK9, body weight, diabetes diagnosis, hypercholesterolemia disease status, dose, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and satin administration were evaluated as potential covariates in the PK model. Baseline total PCSK9, baseline LDL-C, diabetes diagnosis, disease status, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and Statin administration were evaluated as potential covariates in the PD model. RESULTS: LY3015014 PK profile was consistent across all the studies and between healthy subjects and hypercholesterolemia patients. The PK time course data were well described by a two compartment PK model with first order absorption, and covariates identified for PK parameters included weight on both clearance (CL) and central volume (V2), dose on CL, race on bioavailability (F), and age on V2. The PD (LDL-C) was described using an indirect response model with LY3015014 acting to stimulate the elimination of LDL-C. Covariates identified to have a statistically significant impact on PD were coadministration of statins, baseline LDL-C, metabolic syndrome status and gender. CONCLUSIONS: The population PK/PD model adequately describes the PK and PD profiles of LY3015014. Identification of clinically significant covariates will support the design and dose selection for the pivotal registration studies, ensuring that patients are dosed appropriately.

The potent BACE1 inhibitor LY2886721 elicits robust central Aß pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid ß, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ß lowering in nonclinical animal models. Similar potent and persistent amyloid ß lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Profile of an American amateur rugby union sevens series.

BACKGROUND: Rugby union will enter the Olympic arena as Rugby Sevens in 2016. PURPOSE: To investigate the injury rate, injury type, and nature of injuries sustained in an amateur American rugby union sevens tournament series. STUDY DESIGN: Descriptive epidemiology study. METHODS: The rate, demographics, and characteristics of injury were evaluated in 1536 rugby union sevens players, from 128 sides, competing in 4 amateur 1-day tournaments in a USA Rugby local area rugby union. RESULTS: Forty-eight injuries occurred over 4 tournaments, for an injury rate of 55.4 injuries per 1000 playing hours. Head and neck injuries were most common (33.3% of injuries), followed by upper extremity (31.3%), trunk (18.8%), lower extremity (14.6%), and physiologic injuries (2.1%). The most common type of injury was ligament sprain (25.0%); followed by concussion (14.6%), hematoma/contusion (12.5%), muscle strain (10.4%), and abrasion (8.3%). Tackling was the most common mechanism of injury (74.5%). Males were injured at a significantly higher rate than females (RR, 7.5, P < .01), but no significant difference was observed based on player position (P = .08). CONCLUSION: Injuries are common among American amateur rugby athletes, with a substantial proportion involving the head and neck region. CLINICAL RELEVANCE: Understanding injury patterns in an American rugby union will be important for formulating future injury prevention, assessment, and treatment protocols.

The relative timing of exposure to phagocytosable particulates and to osteoclastogenic cytokines is critically important in the determination of myeloid cell fate.

During granulomatous inflammatory reactions, myeloid cells can differentiate into activated phagocytic macrophages, wound-healing macrophages, foreign body giant cells, and bone-resorbing osteoclasts. Although it is appreciated that a variety of stimuli, including cytokines, cell-matrix interactions, and challenge with foreign materials can influence myeloid cell fate, little is known of how these signals integrate during this process. In this study, we have investigated the cross talk between receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis and particle phagocytosis-induced activation of human monocytes. Understanding interconnected signals is of particular importance to disorders, such as periprosthetic osteolysis, in which granulomatous inflammation is initiated by particle phagocytosis in proximity to bone and leads to inflammatory bone loss. Using cell-based osteoclastogenesis and phagocytosis assays together with expression analysis of key regulators of osteoclastogenesis, we show in this study that phagocytosis of disease-relevant particles inhibits RANKL-mediated osteoclastogenesis of human monocytes. Mechanistically, phagocytosis mediates this effect by downregulation of RANK and c-Fms, the receptors for the essential osteoclastogenic cytokines RANKL and M-CSF. RANKL pretreatment of monocytes generates preosteoclasts that are resistant to RANK downregulation and committed to osteoclast formation, even though they retain phagocytic activity. Thus, the relative timing of exposure to phagocytosable particulates and to osteoclastogenic cytokines is critically important in the determination of myeloid cell fate.