Pharmacokinetics of immediate release, extended release, and gastric retentive gabapentin formulations in healthy adults
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OBJECTIVE: Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil extended release formulation (GEn) have been approved for management of postherpetic neuralgia (PHN) in adults. This is the first pharmacokinetic (PK) comparison of all three formulations using FDA-recommended doses for PHN. MATERIALS: This study compared the steady-state PK of GBP-IR 600 mg t.i.d., GBP-GR 1,800 mg q.d., and GEn 600 mg b.i.d. in healthy adults. METHODS: The open-label study consisted of a 3-day lead-in of escalating doses of GBP-IR, 5 days of treatment with each formulation (GPB-IR, GPB-GR, and GEn), and a 7-day taper period on 600 mg GEn q.d.. Plasma concentrations were collected on day 5 for each formulation. PK parameters were estimated from plasma concentration data. RESULTS: 14 healthy subjects (7 men, 7 women; mean (SD) age, 46.8 (7.60) years; mean (SD) body mass index, 26.7 (1.7) kg/m2) received all doses and completed the study. GBP-GR resulted in substantially (~ 4-fold) higher peak-to-trough ratio and percent fluctuation compared to GEn. GEn resulted in more sustained and less fluctuating daily exposure relative to GBP-IR, particularly at the end of 24 hours of dosing. In contrast, gabapentin fluctuation from GBP-IR consisted of 3 distinct peaks. After dose normalization, gabapentin exposure with GEn was ~ 2.2-fold and ~ 1.4-fold higher compared to GBP-GR and GBP-IR, respectively. All treatments were well tolerated. CONCLUSION: GEn requires less frequent dosing compared with GBP-IR and fluctuates less with sustained gabapentin exposure throughout the day. These PK differences may have clinically relevant implications.
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Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects.

AIMS: To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects. METHODS: This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration-time data were analysed using noncompartmental methods. Geometric mean ratios for AUC0-t , AUC0-inf , and peak plasma concentrations (Cmax ) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug-drug interaction if the 90% confidence intervals were outside 80.00-125.00%. RESULTS: Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5 ng ml-1 with neratinib alone to 24.5 ng ml-1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0-t was 1478 ng ml-1  h with neratinib vs. 426 ng ml-1  h with neratinib plus lansoprazole, and geometric LSM AUC0-inf was 1557 ng ml-1  h vs. 542 ng ml-1  h, respectively. Mean t½ was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0-t , AUC0-inf and Cmax fell outside the prespecified equivalence range (80.0-125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects. CONCLUSIONS: Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects.

Disparities in outcomes of COVID-19 hospitalizations in native American individuals.

Objectives: This study aimed to investigate COVID-19-related disparities in clinical presentation and patient outcomes in hospitalized Native American individuals. Methods: The study was performed within 30 hospitals of the Banner Health system in the Southwest United States and included 8,083 adult patients who tested positive for SARS-CoV-2 infection and were hospitalized between 1 March 2020 and 4 September 2020. Bivariate and multivariate analyses were used to assess racial and ethnic differences in clinical presentation and patient outcomes. Results: COVID-19-related hospitalizations in Native American individuals were over-represented compared with non-Hispanic white individuals. Native American individuals had fewer symptoms at admission; greater prevalence of chronic lung disease in the older adult; two times greater risk for ICU admission despite being younger; and 20 times more rapid clinical deterioration warranting ICU admission. Compared with non-Hispanic white individuals, Native American individuals had a greater prevalence of sepsis, were more likely to require invasive mechanical ventilation, had a longer length of stay, and had higher in-hospital mortality. Conclusion: Native American individuals manifested greater case-fatality rates following hospitalization than other races/ethnicities. Atypical symptom presentation of COVID-19 included a greater prevalence of chronic lung disease and a more rapid clinical deterioration, which may be responsible for the observed higher hospital mortality, thereby underscoring the role of pulmonologists in addressing such disparities.

Machine learning-based clinical decision support for infection risk prediction.

Background: Healthcare-associated infection (HAI) remains a significant risk for hospitalized patients and a challenging burden for the healthcare system. This study presents a clinical decision support tool that can be used in clinical workflows to proactively engage secondary assessments of pre-symptomatic and at-risk infection patients, thereby enabling earlier diagnosis and treatment. Methods: This study applies machine learning, specifically ensemble-based boosted decision trees, on large retrospective hospital datasets to develop an infection risk score that predicts infection before obvious symptoms present. We extracted a stratified machine learning dataset of 36,782 healthcare-associated infection patients. The model leveraged vital signs, laboratory measurements and demographics to predict HAI before clinical suspicion, defined as the order of a microbiology test or administration of antibiotics. Results: Our best performing infection risk model achieves a cross-validated AUC of 0.88 at 1 h before clinical suspicion and maintains an AUC >0.85 for 48 h before suspicion by aggregating information across demographics and a set of 163 vital signs and laboratory measurements. A second model trained on a reduced feature space comprising demographics and the 36 most frequently measured vital signs and laboratory measurements can still achieve an AUC of 0.86 at 1 h before clinical suspicion. These results compare favorably against using temperature alone and clinical rules such as the quick sequential organ failure assessment (qSOFA) score. Along with the performance results, we also provide an analysis of model interpretability via feature importance rankings. Conclusion: The predictive model aggregates information from multiple physiological parameters such as vital signs and laboratory measurements to provide a continuous risk score of infection that can be deployed in hospitals to provide advance warning of patient deterioration.

Interpretable Identification of Comorbidities Associated with Recurrent ED and Inpatient Visits.

In the hospital setting, a small percentage of recurrent frequent patients contribute to a disproportional amount of healthcare resource utilization. Moreover, in many of these cases, patient outcomes can be greatly improved by reducing re-occurring visits, especially when they are associated with substance abuse, mental health, and medical factors that could be improved by social-behavioral interventions, outpatient or preventative care. Additionally, health care costs can be reduced significantly with fewer preventable recurrent visits. To address this, we developed a novel, interpretable framework that both identifies recurrent patients with high utilization and determines which comorbidities contribute most to their recurrent visits. Specifically, we present a novel algorithm, called the minimum similarity association rules (MSAR), which balances the confidence-support trade-off, to determine the conditions most associated with re-occurring Emergency department and inpatient visits. We validate MSAR on a large Electronic Health Record dataset, demonstrating the effectiveness and consistency in ability to find low-support comorbidities with high likelihood of being associated with recurrent visits, which is challenging for other algorithms such as XGBoost. Clinical relevance- In the era of value-based care and population health management, the proposal could be used for decision making to help reduce future recurrent admissions, improve patient outcomes and reduce the cost of healthcare.

Early Prediction of Cardiogenic Shock Using Machine Learning.

Cardiogenic shock (CS) is a severe condition with in-hospital mortality of up to 50%. Patients who develop CS may have previous cardiac history, but that may not always be the case, adding to the challenges in optimally identifying and managing these patients. Patients may present to a medical facility with CS or develop CS while in the emergency department (ED), in a general inpatient ward (WARD) or in the critical care unit (CC). While different clinical pathways for management exist once CS is recognized, there are challenges in identifying the patients in a timely manner, in all settings, in a timeframe that will allow proper management. We therefore developed and evaluated retrospectively a machine learning model based on the XGBoost (XGB) algorithm which runs automatically on patient data from the electronic health record (EHR). The algorithm was trained on 8 years of de-identified data (from 2010 to 2017) collected from a large regional healthcare system. The input variables include demographics, vital signs, laboratory values, some orders, and specific pre-existing diagnoses. The model was designed to make predictions 2 h prior to the need of first CS intervention (inotrope, vasopressor, or mechanical circulatory support). The algorithm achieves an overall area under curve (AUC) of 0.87 (0.81 in CC, 0.84 in ED, 0.97 in WARD), which is considered useful for clinical use. The algorithm can be refined based on specific elements defining patient subpopulations, for example presence of acute myocardial infarction (AMI) or congestive heart failure (CHF), further increasing its precision when a patient has these conditions. The top-contributing risk factors learned by the model are consistent with existing clinical findings. Our conclusion is that a useful machine learning model can be used to predict the development of CS. This manuscript describes the main steps of the development process and our results.

A Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Period Crossover Study of the Effects of Solriamfetol on QTcF Intervals in Healthy Participants.

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is approved (United States and European Union; Sunosi) to treat excessive daytime sleepiness associated with narcolepsy (75-150 mg/day) or obstructive sleep apnea (37.5-150 mg/day). A thorough QT/QTc study assessed solriamfetol effects on QT interval (Fridericia correction for heart rate; QTcF). This randomized, double-blind, placebo- and positive-controlled, 4-period crossover study compared single doses of 300 and 900 mg solriamfetol, 400 mg moxifloxacin, and placebo in healthy adults. Placebo- and predose-adjusted mean differences in QTcF (ddQTcF; primary end point) were analyzed, and solriamfetol pharmacokinetics were characterized. Fifty-five participants completed all periods. Upper bounds of 2-sided 90% confidence intervals (CIs) for ddQTcF for both solriamfetol doses were <10 milliseconds at all postdose time points. Assay sensitivity was demonstrated with moxifloxacin; lower bounds of 2-sided 90%CIs for ddQTcF > 5 milliseconds at 1, 2, and 3 hours postdose. There were no QTcF increases > 60 milliseconds or QTcF values > 480 milliseconds at either solriamfetol dose. Solriamfetol median tmax was 2-3 hours; exposure was dose-proportional. More participants experienced adverse events (AEs) after solriamfetol 900 versus 300 mg (70% vs 29%); none were serious (all mild/moderate), and there were no deaths. Common AEs were nausea, dizziness, and palpitations. Neither solriamfetol dose resulted in QTcF prolongation > 10 milliseconds.

A Retrospective Cohort Study of Clinical Factors Associated with Transitions of Care among COVID-19 Patients.

Coronavirus Disease 2019 (COVID-19) is an international health crisis. In this article, we report on patient characteristics associated with care transitions of: 1) hospital admission from the emergency department (ED) and 2) escalation to the intensive care unit (ICU). Analysis of data from the electronic medical record (EMR) was performed for patients with COVID-19 seen in the ED of a large Western U.S. Health System from April to August of 2020, totaling 10,079 encounters. Of these, 5172 resulted in admission as an inpatient within 72 h. Inpatient encounters (n = 6079) were also considered for patients with positive COVID-19 test results, of which 970 resulted in a transfer to the ICU or in-hospital mortality. Laboratory results, vital signs, symptoms, and comorbidities were investigated for each of these care transitions. Different top risk factors were found, but two factors common to hospital admission and ICU transfer were respiratory rate and the need for oxygen support. Comorbidities common to both settings were cerebrovascular disease and congestive heart failure. Regarding laboratory results, the neutrophil-to-lymphocyte ratio was associated with transitions to higher levels of care, along with the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT).

Evaluation of Pharmacokinetic Drug Interactions of the Direct-Acting Antiviral Agents Elbasvir and Grazoprevir with Pitavastatin, Rosuvastatin, Pravastatin, and Atorvastatin in Healthy Adults.

BACKGROUND: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. METHODS: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. RESULTS: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. CONCLUSIONS: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.

Safety, Tolerability, and Pharmacokinetics of the ß-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Verubecestat (MK-8931) in Healthy Elderly Male and Female Subjects.

ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of ß-amyloid peptides, which are implicated in the etiology of Alzheimer's disease. The safety and pharmacokinetics of the BACE1 inhibitor verubecestat have previously been studied in young adults aged 19-45 years. In this randomized, placebo-controlled, phase I study (protocol MK-8931-006), we investigated the safety, tolerability, and pharmacokinetics of a single dose (100 mg) or multiple doses (30, 80, and 120 mg) once daily for 28 days of verubecestat in healthy elderly subjects. Safety end points were assessed at baseline and during the duration of the study period and indicated that verubecestat was generally well tolerated. Verubecestat pharmacokinetics were similar between healthy elderly male and female subjects and similar to those reported in healthy young males in previous studies. These data supported subsequent studies to assess the potential efficacy of verubecestat in subjects with Alzheimer's disease.

A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults.

BACKGROUND: Guanfacine is an alpha(2)-adrenoreceptor agonist used to treat children and adults with attention-deficit/hyperactivity disorder. An extended-release formulation of guanfacine is currently under development. OBJECTIVE: The objective of this study was to assess the single-dose pharmacokinetic properties and dose proportionality of guanfacine extended-release (GXR) tablets after oral administration in healthy adults. METHODS: This was a Phase I, randomized, open-label, single-dose, crossover trial of GXR 1-, 2-, and 4-mg tablets in healthy adults. In the lead-in period (period 1), subjects received a single GXR 1-mg tablet, and then were randomized to receive single GXR 2- or 4-mg tablets during 4 separate weekly visits. Vital signs were monitored, blood samples were obtained, and subjects underwent electrocardiography (ECG) before dose administration and at regular intervals over 96 hours. The pharmacokinetic parameters of CmaX, AUC(0-t), and AUC(0-infinity) were determined after each dose of GXR in all subjects. Summary statistics for the concentration-time data were analyzed to assess between-dose linearity. An analysis-of-variance model was constructed to test the concentration-time data for dose proportionality. Tolerability was assessed at each visit through the analysis of standard serology tests; urinalysis/drug screen reports; and physical examination, including height and weight measurements; vital-sign data; and ECG findings. RESULTS: The total study enrollment was 52 subjects, including 28 men (53.8%) and 24 (46.2%) women. The subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-54 years) and a mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120.0 kg). Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Three subjects were discontinued by the study investigators because of noncompliance with study procedures or use of concomitant medications. Forty-nine subjects completed the study. Mean (SD) values for guanfacine plasma concentrations with GXR 1, 2, and 4 mg, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for C(max); 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL . h(-1) for AUC(0-t); and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL . h(-1) for AUC(0-infinity) . Mean (SD) t((1/2)) values were 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 mg, respectively. The geometric mean ratios for C(max), AUC(0-t), and AUC(0-infinity) were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in C(max) between GXR 1 and 2 mg. All treatment-emergent adverse events (AEs) were assessed as mild or moderate and resolved without treatment with the exception of headache in 3 subjects and 1 case of lower back discomfort, which resolved with therapy. Left rib pain was reported in 1 subject, but it is unknown if it had resolved, since the subject was lost to followup. No subjects withdrew from participation or were discontinued by the study investigators as a result of AEs. The most common treatment-emergent AE, somnolence, occurred in 33 (63.5%) of 52 subjects. All mean vital-sign measurements and mean ECG parameters remained within normal limits after dosing and no marked changes from baseline measurements were noted. Mean values for all test results of hematology and serum chemistry panels were within the reference range at completion of the study, with no significant changes from baseline. CONCLUSIONS: In these 49 healthy adult subjects, the single-dose pharmacokinetic properties of GXR 1-, 2-, and 4-mg tablets appeared to be statistically linear; that is, increases in mean C(max), AUC(0-t), and AUC(0-infinity) of guanfacine were proportional to dose, with the exception of the increase in mean C(max) between GXR 1 and 2 mg. All doses appeared to be well tolerated, with no serious AEs or withdrawal or discontinuation from study participation due to AEs reported.

A Thorough QTc Study Confirms Early Pharmacokinetics/QTc Modeling: A Supratherapeutic Dose of Omarigliptin, a Once-Weekly DPP-4 Inhibitor, Does Not Prolong the QTc Interval.

Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis.

A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic.

Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1-6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect.

Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects.

Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug-drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high-fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80%-125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH-altering agents with cabozantinib is not contraindicated.

Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers.

BACKGROUND/AIMS: To evaluate the ocular hypotensive efficacy, ocular and systemic safety, and systemic exposure of two formulations of 0.5% AR-12286 Ophthalmic Solution. METHODS: This was a double-masked, single-centre, crossover study in 18 normal adult volunteers. Volunteers were randomised to one of two dosing sequences: Formulation A once daily, both eyes (OU) for 8 days, a 7-day minimum washout, and then Formulation B, or the reverse. The main outcome measures were ocular tolerability, intraocular pressure (IOP) and blood levels of AR-12286 and its metabolites. RESULTS: Systemic absorption was low, with a majority of subjects showing no measurable drug concentration in plasma (<1 ng/ml) at any time point with either formulation. The most frequent ocular adverse events were conjunctival hyperaemia, eye irritation, instillation site reaction, increased lacrimation, and blurred vision which were relatively short-lived and judged as not clinically significant. Both formulations of AR-12286 produced substantial reductions from baseline IOP ranging from 3 to 7 mm Hg (p<0.0001). CONCLUSIONS: No differences were noted in ocular safety between formulations of AR-12286 0.5%, dosed once daily in the morning for 8 days. AR-12286 produced little systemic exposure to the parent compound or two known metabolites. Clinically and statistically significant reductions in IOP were seen in these normotensive subjects.

Hemodynamic effect of avanafil and glyceryl trinitrate coadministration.

A Phase I, double-blind, randomized, crossover study in healthy males (N=106) was conducted between March 21, 2004, and May 17, 2004, to determine the magnitude and duration of the hemodynamic interaction of avanafil (a phosphodiesterase type-5 inhibitor for treating males with erectile dysfunction) when coadministered with glyceryl trinitrate (NTG) compared with sildenafil and placebo. Subjects received avanafil (200 mg), sildenafil (100 mg), and placebo (on separate days) via the oral route followed by NTG (0.4 mg) 12, 8, 4, 1, or 0.5 hours post-dose via the sublingual route. Blood pressure (BP) and heart rate (HR) were assessed at defined intervals. Throughout the study (after administration of the study drug, and including the period after NTG administration), the effects of avanafil and sildenafil on BP and HR were significantly greatest overall, at the shortest (0.5-hour) time interval compared with placebo. By the 8- and 12-hour time intervals, no significant difference in BP or HR was observed for avanafil (8 and 12 hours) or sildenafil (12 hours) (p>0.05, compared with placebo). Compared with avanafil, sildenafil had a significantly greater effect when dosed 0.5 hours before NTG on standing HR (p=0.05); 1 hour before NTG on standing systolic blood pressure (SBP) (p<0.05), sitting SBP (p=0.01) and standing HR (p<0.01); and 12 hours before NTG on standing SBP (p=0.05). Throughout the study, symptomatic hypotension adverse events occurred in 27%, 29%, and 12%, and clinically significant reductions in standing SBP (≥30 mmHg) occurred in 15%, 29%, and 12% of subjects dosed with avanafil, sildenafil, and placebo, respectively (overall treatment differences: p<0.01 and p<0.05, respectively). These data show that avanafil and sildenafil have no significant effect on BP and HR if administered to healthy males ≥8 hours (avanafil) or ≥12 hours (sildenafil) before a sublingual dose of NTG. However, results may differ in populations with known vascular disease, especially those using other concurrent pharmacotherapy. These findings may be of interest to clinicians who treat patients with erectile dysfunction and who also have a cardiovascular condition. Of note, the applicability of these results in such patients may be limited because the enrollment comprised healthy, normal subjects.

Randomized, double-masked, placebo-controlled study to assess the ocular safety of mirabegron in healthy volunteers.

PURPOSE: This study assessed the effect of mirabegron on ocular safety in healthy volunteers. METHODS: This was an 8-week, randomized, double-masked, placebo-controlled study. PARTICIPANTS: Consenting adults aged ≥18 years with a normal intraocular pressure (IOP, ≥10 to ≤21 mmHg) were eligible to enter the study. Of the 321 randomized subjects, 305 completed the study. Subjects were randomized 1:1 to a supratherapeutic dose of oral mirabegron 100 mg or placebo once daily for 56 days. The IOP was measured at screening, baseline, day 10, and day 56/end of treatment using Goldmann applanation tonometry. Visual acuity and biomicroscopy were also evaluated. The primary endpoint was the mean change from baseline in the IOP at 56 days or end of treatment with mirabegron versus placebo. Secondary outcome variables included change from baseline to day 10 in the IOP, and increases in the IOP of ≥6 mmHg and ≥10 mmHg in either eye from baseline to day 10 and day 56. RESULTS: The mean (standard error, SE) IOP at baseline was 15.3 (0.16) mmHg for mirabegron and 15.4 (0.16) mmHg for placebo; values at day 56 were 15.0 (0.16) mmHg and 15.2 (0.17) mmHg, respectively. The adjusted mean IOP change from baseline to day 56 was -0.3 mmHg for mirabegron and -0.2 mmHg for placebo (-0.1 mmHg difference [95% confidence interval, CI, -0.4 to 0.3]). For the primary endpoint, mirabegron was noninferior to placebo, based on the prespecified limit of 1.5 mmHg. No statistically significant treatment effects on the IOP were seen at day 10. No subject discontinued due to increased IOP. Clinically significant increases from baseline in the IOP occurred rarely and only with placebo treatment. Changes in the visual acuity and biomicroscopy were not suggestive of a mirabegron effect. No treatment-emergent adverse event (AE) of glaucoma was reported. CONCLUSIONS: Mirabegron 100 mg orally once daily for 8 weeks of treatment does not increase the IOP, and was generally safe and well tolerated.

Evaluation of the effects of bitopertin (RG1678) on cardiac repolarization: a thorough corrected QT study in healthy male volunteers.

BACKGROUND: Bitopertin (RG1678) is a selective glycine reuptake inhibitor currently in Phase III development for the treatment of schizophrenia. Thorough QT studies to assess the effects of candidate drugs on cardiac repolarization and proarrhythmic potential are required by regulatory authorities and are a common part of the drug development process. A clinically relevant effect on QT interval is suspected if prolongation of the corrected QT interval (QTc) is ∼5 milliseconds or more, evidenced by an upper 1-sided 95% CI for the mean effect on the QTc of at least 10 milliseconds. OBJECTIVE: The goal of this study was to investigate the effect of bitopertin on the QTc interval in healthy male volunteers. METHODS: This was a multiple-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study using bitopertin 30 mg (n = 56) or bitopertin 175 mg (n = 56) once daily for 10 days plus placebo on day 11, moxifloxacin 400 mg on day 1 plus placebo once daily for 10 days (n = 29), or placebo once daily for 10 days plus moxifloxacin 400 mg on day 11 (n = 28). Continuous Holter ECGs were obtained on days -1, 1, 10, and 11, and the placebo-corrected mean change from time-matched baseline in the QT interval calculated by using Fridericia's formula (QTcF) on day 10 was the primary end point. Pharmacokinetic parameters of bitopertin were determined on day 10 by using HPLC-MS/MS methods to obtain bitopertin plasma drug concentrations. Adverse events were recorded throughout the study. RESULTS: A total of 169 predominantly white, healthy male volunteers (mean age, 31.8 years; range, 19-59 years) were randomized to treatment; 162 completed the study. The mean change in placebo-corrected QTcF from baseline to day 10 of bitopertin ranged from -2.8 to 3.9 milliseconds. The upper bound of the 1-sided 95% CI was <10 milliseconds at all time points with both doses. There was no relation between bitopertin concentrations and changes in QTcF or other ECG variables. Assay sensitivity was confirmed by a placebo-corrected mean change from time-matched baseline in QTcF of 10.6 milliseconds (lower bound of the 1-sided 98.3% CI, 6.9 milliseconds) 4 hours after moxifloxacin administration. Peak bitopertin plasma concentrations were achieved ∼4 hours after dosing. The terminal elimination t(½) was ∼53 hours. No safety or tolerability concerns were noted with bitopertin at either dose. Dizziness, nausea, and blurred vision were more common in the bitopertin 175-mg group compared with the bitopertin 30-mg or placebo groups. CONCLUSION: Multiple dosing with bitopertin 30 mg or 175 mg did not affect QTcF in these healthy male volunteers. ClinicalTrials.gov identifier: NCT01613040.

Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults.

PURPOSE: To investigate the safety, tolerability, and pharmacokinetics (PKs) of topical SAR 1118 Ophthalmic Solution in healthy adults. SAR 1118 is an investigational small molecule lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLß2) antagonist that inhibits LFA-1 binding to intercellular adhesion molecule-1 (ICAM-1; CD54) targeting T-cell-mediated inflammation. METHODS: A randomized, double-masked, placebo-controlled, dose-escalation study of SAR 1118 was performed in 4 cohorts with 7 randomized subjects per cohort (2 placebo: 5 active drug subjects; 0.1%, 0.3%, 1.0%, 5.0%) in 28 healthy adults. Dosing was divided into 3 periods each separated by a 72-h treatment-free observation: once-daily (QD) × 1, twice-daily (BID) × 10, and thrice-daily (TID) × 10 days. Data obtained at the beginning and end of each period included: slit-lamp, best-corrected visual acuity (BCVA), Schirmer tear test (STT) without anesthesia, tear film break-up time (TBUT), intraocular pressure (IOP), and tear/plasma samples for PK analysis. RESULTS: All subjects completed the study; there were no tolerability issues or missed treatments (total, 1,428 administered doses). No serious ocular or nonocular adverse events (AEs) occurred over 1,148 subject study days (41 days/subject) and no significant abnormalities were identified on ocular exam. There were 38 ocular AEs (N = 11 subjects) and 21 nonocular AEs (N = 11 subjects). Most AEs were mild in severity and occurred in the 0.3% and placebo groups. No changes were observed in CD3, CD4, and CD8 blood lymphocyte counts. Tear PK profiles support a QD/BID dosing schedule. Plasma levels of SAR 1118 in the 0.1% and 0.3% groups were below level of quantitation (BLQ; <0.50 ng/mL) at all time points and transiently detected within the first 5 min to ∼1 h following administration in the 1.0% and 5.0% groups. CONCLUSION: SAR 1118 Ophthalmic Solution appears safe and well-tolerated up to 5.0% TID in healthy adult subjects. PK analysis shows adequate ocular exposure with minimal systemic exposure.

Food effects on the pharmacokinetics of morphine sulfate and naltrexone hydrochloride extended release capsules.

INTRODUCTION: Morphine sulfate and naltrexone hydrochloride extended release capsules, indicated for chronic moderate-to-severe pain, contain extended-release morphine pellets with a sequestered naltrexone core. If pellets are tampered by crushing, naltrexone is released to reduce morphine-induced effects that appeal to opioid abusers. The primary objective of this study was to assess single-dose relative bioavailability of morphine when morphine sulfate and naltrexone hydrochloride extended release capsules were taken under fed and fasting conditions and when pellets were sprinkled on apple sauce. METHODS: This was a single-center, randomized, open-label study in 36 healthy adult volunteers. Subjects took a 100-mg morphine sulfate and naltrexone hydrochloride extended release capsule intact with 240 mL water, under fed and fasted conditions, and when the capsule was opened and pellets were sprinkled over apple sauce and consumed without chewing; each treatment was separated by a 14-day washout. Plasma samples were collected just before dosing through 72 hours postdose for pharmacokinetic analyses of morphine, and through 168 hours postdose for naltrexone and its major metabolite 6-ß-naltrexol. RESULTS: Morphine bioavailability was similar for all treatments. There was a lack of sprinkle effect (sprinkle vs. whole, fasted); 90% confidence intervals (CIs) of ratios of log-transformed least squares means for area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) fell within 80%-125% boundaries. For the food effect, 90% CIs were within the boundaries for AUC, but C(max) was reduced and time to C(max) was delayed by 2.5 hours under fed conditions. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure. CONCLUSION: Results indicated that morphine sulfate and naltrexone hydrochloride extended release capsules can be administered without regard to meals, and contents can be sprinkled over apple sauce and consumed without chewing by patients with difficulty swallowing.