Intelligent Approach to Network Device Migration Planning towards Software-Defined IPv6 Networks.

Internet and telecom service providers worldwide are facing financial sustainability issues in migrating their existing legacy IPv4 networking system due to backward compatibility issues with the latest generation networking paradigms viz. Internet protocol version 6 (IPv6) and software-defined networking (SDN). Bench marking of existing networking devices is required to identify their status whether the existing running devices are upgradable or need replacement to make them operable with SDN and IPv6 networking so that internet and telecom service providers can properly plan their network migration to optimize capital and operational expenditures for future sustainability. In this paper, we implement "adaptive neuro fuzzy inference system (ANFIS)", a well-known intelligent approach for network device status identification to classify whether a network device is upgradable or requires replacement. Similarly, we establish a knowledge base (KB) system to store the information of device internetwork operating system (IoS)/firmware version, its SDN, and IPv6 support with end-of-life and end-of-support. For input to ANFIS, device performance metrics such as average CPU utilization, throughput, and memory capacity are retrieved and mapped with data from KB. We run the experiment with other well-known classification methods, for example, support vector machine (SVM), fine tree, and liner regression to compare performance results with ANFIS. The comparative results show that the ANFIS-based classification approach is more accurate and optimal than other methods. For service providers with a large number of network devices, this approach assists them to properly classify the device and make a decision for the smooth transitioning to SDN-enabled IPv6 networks.

Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine.

This single-dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2-drug, fixed-dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single-entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration-time curve (AUC) and maximum concentration (Cmax ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC0-∞ and Cmax ) and lamivudine (AUC0-∞ and AUC0-t ) exposure; however, dolutegravir AUC0-t and lamivudine Cmax were approximately 16% and 32% higher than the reference, respectively. A high-fat meal increased dolutegravir AUC and Cmax by up to 33% and 21%, respectively, and decreased lamivudine Cmax by approximately 30%. Both test and reference formulations were well tolerated. The results support further development of formulation AK as a novel, 2-drug, fixed-dose combination tablet treatment for patients with HIV.

Effects of Low- and High-Mineral Content Water on the Relative Bioavailability of a Coformulated Abacavir/Dolutegravir/Lamivudine Dispersible Tablet in Healthy Adults.

BACKGROUND: The fixed-dose combination (FDC) tablet formulation of abacavir/dolutegravir/lamivudine is indicated for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥40 kg. Alternative formulations with acceptable palatability and convenient dosing are needed for children who require smaller doses and have difficulty swallowing tablets. SETTING: A phase 1, open-label, randomized study was conducted in healthy adults to evaluate the relative bioavailability of a novel dispersible FDC tablet of abacavir 150 mg/dolutegravir 10 mg/lamivudine 75 mg administered under 4 different dosing conditions compared with dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. METHODS: The test treatments were 4 dispersible FDC tablets reconstituted in water with high- or zero-mineral content and administered either immediately or after a 30-minute delay. The reference treatment was 4 nondispersible dolutegravir 10-mg tablets plus 1 nondispersible abacavir 600-mg/lamivudine 300-mg tablet administered with zero-mineral content water. The primary endpoints were area under the concentration-time curve from time 0 extrapolated to infinity and the maximum observed plasma concentration. RESULTS: Following administration of dispersible abacavir/dolutegravir/lamivudine, the relative bioavailability of dolutegravir was approximately 50% higher. Abacavir and lamivudine demonstrated bioequivalence when administered as the dispersible FDC tablet compared with coadministration of dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. Neither the mineral content of the water nor dosing times affected the pharmacokinetics of individual components. The dispersible tablet was safe and well tolerated, and the palatability was acceptable. CONCLUSIONS: These pharmacokinetic results support further development of a dispersible FDC tablet of abacavir/dolutegravir/lamivudine for future use in pediatric patients.

Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial.

BACKGROUND: Fluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action. METHODS: A single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation. RESULTS: In the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42-212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61-0.86) with the maximum reduction occurring at day 14, 0.32 (0.27-0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59-1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment. CONCLUSIONS: The anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma. Funding GlaxoSmithKline (201499). TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov registry number NCT02712047 .

Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.).

Pharmacokinetic Comparison of a Unit Dose Dry Powder Inhaler with a Multidose Dry Powder Inhaler for Delivery of Fluticasone Furoate.

BACKGROUND: The unit dose dry powder inhaler (UD-DPI) is being considered as an alternative inhaler platform that, if developed, has the potential to improve access to inhaled respiratory medicines in developing countries. AIM: This study compared the systemic exposure of fluticasone furoate after delivery from the UD-DPI with that from the ELLIPTA® inhaler. METHODS: This open-label, five-way cross-over, randomized, single-dose study in healthy subjects evaluated fluticasone furoate systemic exposure of three dose strengths (using four inhalations), 4 × 80 µg [320 µg], 4 × 100 µg [400 µg], and 4 × 140 µg [560 µg]), and two percentages of drug in lactose blends (0.6% and 0.8% by weight) after delivery from the UD-DPI compared with systemic exposures from the ELLIPTA inhaler (4 × 100 µg [400 µg] dose, 0.8% lactose blend). The primary treatment comparisons were area under the concentration-time curve from time 0 to 6 hours [AUC0-6] and maximum plasma concentration [Cmax]. RESULTS: After single-dose administration of fluticasone furoate, systemic exposure was lower from all UD-DPI formulations versus the ELLIPTA inhaler in terms of both AUC0-6 [AUC0-6 geometric least squares mean (GLM) ratios confidence interval (90% CI) for: UD-DPI (400 µg 0.8% blend)/ELLIPTA: 0.61 (0.55-0.67) and Cmax GLM (90% CI) for: UD-DPI (400 µg 0.8% blend)/ELLIPTA: 0.56 (0.49-0.64)]. Systemic exposures were ∼10% lower for fluticasone furoate UD-DPI for the 0.8% blend versus the 0.6% blend [GLM ratio (90% CI); 0.90 (0.81-1.00) for AUC0-6 and 0.89 (0.77-1.01) for Cmax], and increasing doses of fluticasone furoate from the UD-DPI showed systemic exposures that were approximately dose proportional. All treatments were well tolerated. CONCLUSIONS: Fluticasone furoate systemic exposure was lower from the UD-DPI than from the ELLIPTA inhaler, but the UD-DPI formulations did demonstrate detectable systemic levels and approximate dose proportionality. Together with the good tolerability shown, these data support further evaluation of the UD-DPI as a potential device for delivering inhaled respiratory drugs.

Pharmacokinetics of Salbutamol Delivered from the Unit Dose Dry Powder Inhaler: Comparison with the Metered Dose Inhaler and Diskus Dry Powder Inhaler.

AIM: To compare the systemic exposure of salbutamol following delivery from the unit dose dry powder inhaler (UD-DPI) system with that from the Diskus® and metered dose inhaler (MDI). MATERIALS AND METHODS: This open-label, two-part, six-way crossover, randomized single-dose study in healthy subjects evaluated salbutamol systemic exposure of three dose strengths (using three inhalations: 3 × 150 µg [450 µg], 3 × 200 µg [600 µg], and 3 × 250 µg [750 µg]) and 2% of drug in lactose blends (1.6% and 1.0% [600 µg dose only] by weight) following delivery through the UD-DPI compared with systemic exposure from the Diskus and MDI (600 µg dose). Systemic exposure in the presence of charcoal block was also evaluated. Primary treatment comparisons were area under the concentration-time curve from time zero to 12 hours [AUC0-12] and maximum plasma concentration [Cmax]. RESULTS: Delivery of salbutamol 600 µg from the UD-DPI resulted in total systemic exposure similar to that from the Diskus and approximately half of that from the MDI (AUC0-12 geometric least squares mean ratio [GMR] [90% confidence interval (CI)] for UD-DPI [1.6% blend]/Diskus: 0.91 [0.83-1.00]; UD-DPI [1.6% blend]/MDI: 0.46 [0.42-0.50]. Cmax GMR [90% CI] for UD-DPI [1.6% blend]/Diskus: 1.20 [1.07-1.33]; UD-DPI [1.6% blend]/MDI: 0.58 [0.52-0.64]). Results were consistent between the 1.6% and the 1.0% blends and systemic exposure for the 3 dose strengths of salbutamol (1.6% blend) showed increases that were 12-16% greater than dose proportional. Systemic exposure due to pulmonary absorption (as calculated from AUC0-12 in the presence and absence of charcoal block) was 48% for the UD-DPI, 24% for Diskus, and 37% for MDI of the total salbutamol systemic exposure, and the corresponding estimated lung dose was 65% for the UD-DPI and 34% for the Diskus relative to the MDI. CONCLUSIONS: Salbutamol total systemic exposure following UD-DPI was similar to that from the Diskus and was lower than that following the MDI. The different blend formulations tested resulted in consistent salbutamol systemic exposure. The contribution of the lung and gut to systemic exposure revealed a different profile for the three inhaler platforms. These data suggest that the UD-DPI warrants further evaluation.

Pharmacokinetic and Bioequivalence Studies of a Newly Developed Branded Generic of Candesartan Cilexetil Tablets in Healthy Volunteers.

Two bioavailability/bioequivalence studies were carried out to evaluate the pharmacokinetics of candesartan cilexetil 16-mg tablet formulations. A pilot study was used to optimize the formulation and manufacturing process prior to conducting the definitive study. The pilot study was a single-dose, randomized, 2-period crossover, and the definitive study was a single-dose, randomized, 3-period, 6-sequence crossover study in healthy adults. In the pilot study the test formulation was 24% and 18% greater for Cmax and AUC, respectively, compared with the innovator product. Following optimization two 16-mg candesartan cilexetil tablet formulations were taken forward into the second bioavailability study.  Eighteen healthy fasted adult subjects were dosed with either the test formulations or the innovator. The pharmacokinetic parameters Cmax , AUC0-t , and AUC0-∞ of candesartan were investigated together with safety and tolerability. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for candesartan, Cmax , AUC0-t , and AUC0-∞ were within the boundary of 0.8-1.25 for one of the test formulations (formulation 2). For test formulation 3 the 90%CI of GMR for Cmax was above (133%) the upper limit of 125% for bioequivalence. Test formulation 2 was found to be bioequivalent and met internationally acceptable regulatory requirements.

The relative bioavailability of 2 prototype fixed-dose combination formulations for amlodipine and rosuvastatin in healthy white and Chinese subjects.

A fixed-dose combination (FDC) may improve patient compliance and clinical outcomes in the management of cardiovascular risk in hypertensive and dyslipidemic patients. The study (NCT02075619) evaluated the bioavailability of 2 prototype FDC tablet formulations (FDC1 and FDC2) of amlodipine/rosuvastatin (10 mg/20 mg) compared with coadministered reference tablets. It was a randomized, single-dose, 3-way crossover pilot study in healthy white (n = 12) and Chinese (n = 12) adults. Three treatments (FDC1, FDC2, and reference) were administered after fasting with a washout period of 12-17 days. The pharmacokinetics of amlodipine and rosuvastatin were studied for all subjects (pooled) and by ethnicity. Safety and tolerability were also evaluated. Both FDCs met the bioequivalence criteria (90% confidence intervals falling within the range of 0.80-1.25) for AUC0-t and Cmax for amlodipine and rosuvastatin. Intrasubject variability (AUC0-t and Cmax ) was in the region of 23%-25% for rosuvastatin and 7%-10% for amlodipine. The FDC formulations demonstrated similar bioavailability to coadministered commercially available amlodipine and rosuvastatin. All treatments were generally well tolerated.

Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis.

BACKGROUND: Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC). METHODS: Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin. RESULTS: Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score ≤2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures. CONCLUSIONS: SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted.