Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC₅₀] = 0.18 nM) or B/Yamagata (IC₅₀ = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC_0–24), minimum concentration of OC in plasma (C_min), and maximum concentration of OC in plasma (C_max). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC_0–24 evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC_0–24 threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.     

Analysis of Genetic Diversity of Indian Tea Accessions Using Two Modified Amplified Fragment Length Polymorphism Methods

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - The authors compared the utility of two variants of Amplified Fragment Length Polymorphism (AFLP) technique,...     

Loteprednol Etabonate Ophthalmic Gel 0.5% Following Cataract Surgery: Integrated Analysis of Two Clinical Studies

Introduction

We aimed to evaluate the safety and efficacy of loteprednol etabonate (LE) gel 0.5% compared with vehicle in the treatment of postoperative inflammation and pain following cataract surgery, using the integrated analysis of data from two identical, prospective, multicenter, randomized, double-masked, parallel-group, vehicle-controlled trials.

Methods

Patients with anterior chamber cell (ACC) inflammation ≥ grade 2 (6–15 cells) 1 day post-surgery were randomized to receive 1 or 2 drops of LE gel 0.5% or vehicle 4 times per day instilled in the study eye for 14 days. Primary outcome measures included the proportion of patients with complete resolution of ACC and grade 0 (no) pain on postoperative Day 8. Safety endpoints included adverse events (AEs), changes from baseline in intraocular pressure (IOP) and visual acuity (VA), biomicroscopy, and funduscopy findings. Gel comfort was graded by patients according to drop sensation.

Results

The intent-to-treat population included 813 patients (409 LE gel 0.5% and 404 vehicle). At postoperative Day 8, 30.8% and 15.1% of patients randomized to LE gel 0.5% or vehicle, respectively, had complete resolution of ACC, while 74.3% and 43.8% of patients, respectively, had grade 0 pain (P < 0.001 for both). Tolerability assessments for ocular itching, photophobia, and tearing favored LE gel 0.5% compared with vehicle at different time points beginning at Day 3. Two patients in the LE gel 0.5% group and 1 patient in the vehicle group exhibited a transient treatment-emergent increase in IOP ≥ 10 mmHg. Treatment-related AEs were generally mild to moderate and occurred less frequently with LE gel 0.5% than with vehicle. Reports of treatment-related blurred vision were rare (n = 2, vehicle).

Conclusion

LE gel 0.5% was efficacious and well tolerated in the treatment of postoperative pain and inflammation following ocular surgery, with minimal risk of IOP elevation.     

Safety and Efficacy of Mirogabalin for Peripheral Neuropathic Pain: Pooled Analysis of Two Pivotal Phase III Studies

PurposeMirogabalin besylate has been approved in several countries to treat peripheral neuropathic pain. This pooled analysis, using data from the two pivotal Phase III studies in Asian patients with diabetic peripheral neuropathic pain and post-herpetic neuralgia, aimed to provide clinicians with more detailed and precise information relating to mirogabalin's safety and efficacy.MethodsData were pooled from 2 multicenter, double-blind, placebo-controlled, parallel-group, 14-week treatment studies of mirogabalin conducted at ∼350 study sites (Japan, South Korea, Taiwan, Singapore, Malaysia, and Thailand). Eligible patients in both studies were randomized in a 2:1:1:1 ratio, stratified according to a baseline average daily pain score (ADPS) of <6 or ≥6, to placebo, mirogabalin 15-mg once daily (QD), mirogabalin 10-mg twice daily (BID), or mirogabalin 15-mg BID treatment groups. Safety was assessed based on treatment-emergent adverse events identified from the adverse events collected throughout both studies. The primary efficacy end point of both studies was the change from baseline in ADPS at week 14.FindingsIn total, 1587 patients (824 with diabetic peripheral neuropathic pain; 763 with post-herpetic neuralgia) who received at least 1 dose of study drug were analyzed (633 received placebo, 954 treated with mirogabalin). Treatment-emergent adverse events included somnolence (3.8%, 10.8%, 14.5%, and 19.1%) and dizziness (2.7%, 5.7%, 9.1%, and 13.1%) in patients receiving placebo, mirogabalin 15 mg QD, mirogabalin 10 mg BID, and mirogabalin 15 mg BID, respectively. In patients treated with mirogabalin 15 mg QD, 2 (0.6%) of 316 patients discontinued due to somnolence. In the mirogabalin 10-mg BID group, somnolence, edema, and peripheral edema each resulted in 3 (0.9%) of 318 patient discontinuations. In the mirogabalin 15-mg BID group, 6 (1.9%) of 320 patients discontinued due to dizziness and 3 (0.9%) due to somnolence. At week 14, mirogabalin 10 mg BID and 15 mg BID statistically significantly improved ADPS versus placebo, with least squares mean changes (95% CI) of −0.31 (−0.55, −0.08) and −0.63 (−0.86, −0.40). Post hoc analysis showed a statistically significant difference 2 days after administration in the mirogabalin 10-mg and 15-mg BID groups compared with placebo. Female sex, age ≥65 years, and baseline weight <60 kg may influence the safety of mirogabalin, particularly regarding the incidence of somnolence and dizziness, but had no notable impact on efficacy. ClinicalTrials.gov identifiers: NCT02318706 and NCT02318719.ImplicationsThis pooled analysis showed that mirogabalin was efficacious and well-tolerated by Asian patients with peripheral neuropathic pain.     

Population Pharmacokinetic Analysis for a Single 1,200-Milligram Dose of Oritavancin Using Data from Two Pivotal Phase 3 Clinical Trials

Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r² = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC_0–72) and maximum plasma concentration (C_max) were 1,530 (36.9%) μg · h/ml and 138 (23%) μg/ml, respectively. The mean (CV) half-life at alpha phase (t_1/2α), t_1/2β, and t_1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status.     

The Speed of Sound in Rat Liver With Steatohepatitis: Ex Vivo Analysis Using Two Types of Ultrasound Systems

We have previously reported a non-invasive method that would be clinically applicable for measurement of speed of sound (SOS) in the liver. The objective of the present study was to confirm the utility of this new method for assessing over time the SOS in liver with progressive steatohepatitis of different grades and stages. Rats were divided into two groups—a control group and a steatohepatitis group—prepared by keeping the rats on a methionine and choline-deficient diet for 43 wk. The SOS through the liver tissue was measured using the new method in comparison with a pulse-receiver as the standard. The SOS through liver with steatohepatitis temporarily decreased with the fat deposition level and then increased in parallel with the progression of inflammation and fibrosis. Monitoring the change in SOS through liver tissue in individual patients with fatty liver would have considerable potential for assisting the non-invasive detection of early-stage steatohepatitis.     

An Evaluation of the Effectiveness of a Transdiagnostic Bibliotherapy Program for Anxiety and Related Disorders: Results From Two Studies Using a Benchmarking Approach

Anxiety and related disorders are common and cognitive behavior therapy (CBT) has been demonstrated to be an effective treatment for these disorders. However, patients face many barriers to accessing this treatment. Remote delivery of treatment using bibliotherapy-administered CBT (BCBT) has the potential to increase accessibility to evidence-based treatment for patients with anxiety and related disorders. This study investigated the effectiveness of a transdiagnostic BCBT intervention in two open trials. While the BCBT intervention in both studies were identical, the first study was unguided (i.e., no clinician support provided), and the second study was guided (i.e., patients were provided with brief clinician support via telephone). Twenty-three participants with mixed anxiety disorders completed the first Study (unguided treatment) and results exhibited significant reductions on the primary outcome measure with within-group effect sizes of d?=?1.29 (95% CI 0.64–1.91) at post-treatment and d?=?1.52 (95% CI 0.84–2.15) at 3-month follow up. Forty-one participants with various anxiety and related disorders completed Study 2 (guided intervention) and results were similar to Study 1 with large within-group effect sizes seen at post-treatment (d?=?0.95; 95% CI 0.49–1.40) and 3-month follow up (d?=?0.87; 95% CI 0.41–1.31). In both studies participants found the intervention to be highly acceptable, and benchmarking analyses indicated that the outcomes were largely consistent with those of controlled trials. These are the first studies to investigate the effectiveness of a transdiagnostic BCBT program for the treatment of anxiety and related disorders and the results demonstrate preliminary support for this treatment methodology.     

Amlodipine Toxicity in Children Less Than 6 Years of Age: A Dose-Response Analysis Using National Poison Data System Data

Background: Amlodipine is a long-acting calcium channel blocker capable of producing hypotension and dysrhythmia in overdose. The toxic doses of amlodipine in children are unclear. Objectives: The purposes of this study were to describe amlodipine poisoning in children and to determine whether a dose-response relationship could be detected in this population using standardized call data from United States (US) poison centers. Patients and Methods: 1251 amlodipine-only ingestions in children < 6 years of age were reviewed. Cases with doses coded as “Exact” or “Estimated” and with dose, age, and medical outcome were analyzed (n = 678). Ingestions reported as a “taste or lick” (n = 53) were included as a dose of 1/10 of the dosage form involved. A clinically important response was defined as bradycardia, hypotension, dysrhythmia, conduction disturbance, or hyperglycemia. The risk of such responses was examined over four dosage intervals (< 2.5 mg, 2.5–5 mg, 5.1–10 mg, and > 10 mg). Results: The median estimated dose ingested was 5 mg (range 0.25–200 mg). Clinically important responses developed in 27 patients (3.98%), and the prevalence of such response significantly increased from 0% for the lowest to 11.1% for the highest dose interval (p = 0.001). The smallest dose to produce a clinically important response was 2.5 mg (0.15 mg/kg). Children who ingested > 10 mg were 4.4 times more likely to develop clinically important responses than those ingesting ≤ 5 mg. Conclusion: Hypotension may occur in children with amlodipine doses as low as 2.5 mg. The National Poison Data System might provide useful insights regarding dose-response.     

Self-discrepancy as a Predictor of Eating Disorder Symptoms: Findings from Two Ecological Momentary Assessment Studies of Adults with Binge Eating

Cognitive Therapy and Research - Self-discrepancy theory suggests that discrepancies between one’s actual, ideal, and ought self can generate negative affective states and are associated with...     

Location of Pathogenic Bacteria during Persistent Infections: Insights from an Analysis Using Game Theory

Bacterial persistent infections are responsible for a significant amount of the human morbidity and mortality. Unlike acute bacterial infections, it is very difficult to treat persistent bacterial infections (e.g. tuberculosis). Knowledge about the location of pathogenic bacteria during persistent infection will help to treat such conditions by designing novel drugs which can reach such locations. In this study, events of bacterial persistent infections were analyzed using game theory. A game was defined where the pathogen and the host are the two players with a conflict of interest. Criteria for the establishment of Nash equilibrium were calculated for this game. This theoretical model, which is very simple and heuristic, predicts that during persistent infections pathogenic bacteria stay in both intracellular and extracellular compartments of the host. The result of this study implies that a bacterium should be able to survive in both intracellular and extracellular compartments of the host in order to cause persistent infections. This explains why persistent infections are more often caused by intracellular pathogens like Mycobacterium and Salmonella. Moreover, this prediction is in consistence with the results of previous experimental studies.     

Quantitative Analysis of Helical Flow with Accuracy Using Ultrasound Speckle Image Velocimetry: In Vitro and in Vivo Feasibility Studies

Venous valve dysfunction and induced secondary abnormal flows are closely associated with venous diseases. Thus, detailed analysis of venous valvular flow is invaluable from biological and medical perspectives. However, most of the previous studies on venous perivalvular flows were based on qualitative analysis. On the contrary, quantitative analysis of perivalvular flows has not been fully understood. In this study, we used the ultrasound speckle image velocimetry (SIV) technique, which utilizes the speckle patterns of red blood cells (RBCs) created by ultrasound waves to measure 3-D valvular flows quantitatively. The flow structures obtained with the proposed SIV technique for an in vitro model were compared with those obtained by numerical simulation and the color Doppler method to validate the measurement accuracy of the ultrasound SIV technique. Blood flow in the human great saphenous vein was then measured at various distances from the valve with and without exercise. 3-D valvular flow was analyzed in accordance with the dimensionless index, helical intensity. The results obtained by the proposed method matched well with those obtained by numerical simulation and the color Doppler method. The hemodynamic characteristics of 3-D valvular helical flow which were analyzed experimentally using the SIV method would be used for quantitative diagnosis of venous valvular diseases.     

Using Patient Feedback to Optimize the Design of a Certolizumab Pegol Electromechanical Self-Injection Device: Insights from Human Factors Studies

Introduction

We incorporated patient feedback from human factors studies (HFS) in the patient-centric design and validation of ava^®, an electromechanical device (e-Device) for self-injecting the anti-tumor necrosis factor certolizumab pegol (CZP).

Methods

Healthcare professionals, caregivers, healthy volunteers, and patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or Crohn’s disease participated in 11 formative HFS to optimize the e-Device design through intended user feedback; nine studies involved simulated injections. Formative participant questionnaire feedback was collected following e-Device prototype handling. Validation HFS (one EU study and one US study) assessed the safe and effective setup and use of the e-Device using 22 predefined critical tasks. Task outcomes were categorized as “failures” if participants did not succeed within three attempts.

Results

Two hundred eighty-three participants entered formative (163) and validation (120) HFS; 260 participants performed one or more simulated e-Device self-injections. Design changes following formative HFS included alterations to buttons and the graphical user interface screen. All validation HFS participants completed critical tasks necessary for CZP dose delivery, with minimal critical task failures (12 of 572 critical tasks, 2.1%, in the EU study, and 2 of 5310 critical tasks, less than 0.1%, in the US study).

Conclusion

CZP e-Device development was guided by intended user feedback through HFS, ensuring the final design addressed patients’ needs. In both validation studies, participants successfully performed all critical tasks, demonstrating safe and effective e-Device self-injections.

Funding

UCB Pharma.

Plain Language Summary

Plain language summary available on the journal website.

     

National and Regional Market Penetration Rates of Generic's High Dosage Buprenorphine: Its Evolution from 2006 to 2008, Using Reimbursed Drug Database

Objective. To assess the national market penetration rate (PR) of generic high-dosage buprenorphine (HDB) in 2008 and its evolution since their marketing (2006), and making a point for each dosage and at regional level. Methods. Retrospective study over data using national and regional health reimbursement database over three years (2006-2008). Results. In 2008, the generic HDB's national MPR was 31%. The PR for each dosage were 45% for 0.4 mg, 36% for 2 mg and 19% for 8 mg. The (PR) based on Defined Daily Dose (DDD) was 23% in 2008, 15% in 2007 and 4% in 2006. In 2008, at the regional level, disparities were observed in the adjusted penetration rate from 15% in ?le de France to 39% in Champagne Ardennes Lorraine. Conclusion. The national PR of generic HDB has increased. There are differences in MPR in terms of dosage and area. However, this PR is still low (in 2008, 82% of the delivered drugs are generics).