Bid Formulation Research Articles

A Bioequivalence Comparison at Steady State between the Newly Developed Once-Daily Extended Release Tablet Formulation and the Approved Twice-Daily Tablet Formulation of Deutetrabenazine (P2-11.015)

<h3>Objective:</h3> To assess the bioequivalence (BE) and relative bioavailability (BA) between a once-daily (QD) extended release formulation of deutetrabenazine and the approved twice-daily (BID) formulation at steady state under fed conditions. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva) in a BID formulation is an approved treatment for tardive dyskinesia and chorea associated with Huntington disease. A QD formulation has been developed. <h3>Design/Methods:</h3> In a phase 1 study (TV50717-BE-10179) using a randomized cross-over design, healthy adult males and females (n=262) received 24 mg QD formulation (test) as a once daily administration and 12 mg BID formulation (reference) as a twice daily administration, each for 7 days in fed state. Safety was assessed throughout the study and pharmacokinetic (PK) blood sampling occurred on days 4–7. Test-to-reference geometric mean ratios (GMRs) and 90%CIs for BE acceptance limits (80.00% to 125.00%) were computed for PK parameters (area under the plasma concentration curve over 24-hours at steady-state [AUC_0–24hr,ss] and maximum plasma concentration at steady-state [C_max,ss]) of deutetrabenazine, active metabolites, deuterated α-HTBZ and β-HTBZ, and total (α+β)-HTBZ. Relative BA was assessed for C_max,ss of the active metabolites (individually and as a total sum). <h3>Results:</h3> The GMRs (90%CIs) for AUC_0–24hr,ss were 115.15% (110.38–120.14%) for deutetrabenazine, 95.40% (94.13–96.69%) for α-HTBZ, 94.13% (92.35–95.94%) for β-HTBZ, and 95.05% (93.67–96.46%) for total (α+β)-HTBZ. GMRs of C_max,ss were 95.09% (90.60–99.80%) for deutetrabenazine, 79.56% (78.21–80.94%) for α-HTBZ, 74.85% (73.13–76.60%) for β-HTBZ and 77.71% (76.26–79.16%) for total (α+β)-HTBZ. No new safety findings emerged in this study. <h3>Conclusions:</h3> At steady state, deutetrabenazine administered as the QD formulation was bioequivalent to the approved BID formulation for both AUC and C_max. The active metabolites at steady state were bioequivalent with regard to AUC between the QD and BID formulation; C_max was slightly lower for the QD formulation compared to the BID formulation. <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gutierrez has stock in Teva. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals.

Assessment of Dose Proportionality of Three Dose Strengths (6 mg, 12 mg and 24 mg) over the Clinical Dose Range (6–48 mg) of the Newly Developed Once-Daily Extended Release Tablet Formulation of Deutetrabenazine (P2-11.016)

<h3>Objective:</h3> To assess dose proportionality of three dose strengths (6mg, 12mg and 24mg), and across recommended clinical dose range (6mg – 48mg), for the once-daily (QD) extended-release tablet formulation of deutetrabenazine. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva), a twice-daily (BID) formulation, is an approved treatment (daily doses 6–48mg) for tardive dyskinesia and chorea associated with Huntington disease. The new QD formulation has shown to deliver similar daily exposure to the BID formulation. <h3>Design/Methods:</h3> In a randomized phase 1 study (Study TV50717-PK-10175), healthy adult males and females (n=116) received single administrations of the QD formulation in a fed state (2×6mg, 1×12mg, 1×24mg, 2×24mg). Safety was assessed, and pharmacokinetic (PK) blood samples were collected pre-dose and up to 96 hours post-dose. Geometric mean ratios (GMRs) and 90% CIs were computed for PK parameters (maximum plasma concentration [C_max], area under the plasma concentration curve from time 0 to 36 hours [AUC_0–36h] and extrapolated to infinity [AUC_0-inf]) of deutetrabenazine, and active metabolites, deuterated α-HTBZ and β-HTBZ (individually and as a sum). A power model was fitted to describe the relationship between dose and PK parameters using a mixed model with sequence, period, and dose as fixed effects; and subject as random effect. To determine dose proportionality starting at 6mg, relative bioavailability was assessed between 2×6mg and 1×12mg. <h3>Results:</h3> GMRs and 90% CIs for C_max and AUCs fell within the bioequivalence limits of 80.00%–125.00%, demonstrating similarity between 2×6mg and 1×12mg tablets. Dose proportionality was demonstrated for all PK parameters and all analytes for QD formulation dose strengths 6mg, 12mg, and 24mg; and over the clinical dose range (6–48mg), as the 90% CIs for the slopes were contained within 0.839 to 1.161 and 0.839 to 1.107, respectively. <h3>Conclusions:</h3> The QD formulation of deutetrabenazine exhibits dose proportional pharmacokinetics for dose strengths (6mg, 12mg and 24mg), and across the full clinical dose range (6mg – 48mg). <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Dr. Gutierrez has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals.

Designing a transactive electric vehicle agent with customer’s participation preference

The proliferation of electric vehicles (EVs) and their inherent flexibility in charging timings make them an asset to improve grid performance. In contrast to direct control by a utility or autonomous price-based charging, the transactive control framework not only provides benefits to both grid and customers but also ensures customer autonomy. In this work, we design a transactive electric vehicle (TEV) agent that incorporates the EV owner’s willingness to trade-off between savings and amenity in form of a slider, where the EV owner’s amenity is characterized as vehicle readiness. Further, a privacy-preserving bidding formulation is proposed that also represents the customer’s transactive preference. A transactive market mechanism is discussed that integrates the TEV Agents into the local retail market and reconciles with the current day-ahead and real-time market structure. It is demonstrated that the proposed slider is able to provide a preferred trade-off between savings and amenity to individual customers. At the same time, the market mechanism is shown to successfully reduce both peak prices and peak demand. A comparative investigation of V1G and V2G technologies with respect to the battery prices is also discussed. It reveals that the V2G does not offer significant additional benefits with current battery prices, but could be promising if battery costs decline in the future.

Therapeutic equivalence of vildagliptin 100 mg once daily modified release to 50 mg twice daily immediate release formulation: An open-label, randomized, two-period, single- and multiple-dose, 6-day crossover study

Background and aimsVildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor to treat type 2 diabetes mellitus, is available as immediate release (IR) tablets administered at 50 mg twice daily (BID). A 100 mg modified release (MR) formulation was developed for once daily (QD) dosing. This study aimed to compare the therapeutic equivalence of vildagliptin 100 mg MR QD (test) and 50 mg IR BID (reference) formulations at steady state under fasting conditions. MethodsThis was an open-label, randomized, two-period, single- and multiple-dose, two-way crossover, steady state study conducted in healthy adult subjects. Both vildagliptin formulations were administered for six days. Endpoints included pharmacodynamic equivalence, pharmacokinetic parameters, and tolerability of both formulations. ResultsThirty subjects were enrolled and 26 completed both treatments. Maximum plasma concentration and exposure achieved with test was lower than reference formulation on day 1 and 6. The DPP-4 enzyme inhibition over time (DPP-4-AUEC0-24) was comparable between the formulations. Both formulations were well tolerated. ConclusionThis study confirms the therapeutic equivalence of vildagliptin IR and MR formulations for DPP-4 enzyme inhibition over time. The study supports vildagliptin 100 mg MR QD as a useful therapeutic alternative to 50 mg IR BID formulation to possibly improve treatment adherence and patient compliance. Long-term safety of the vildagliptin 100 mg MR QD formulation is not evaluated in this study.

Iterative Multi-Attribute Procurement Auction with Decision Support for Bid Formulation

Iterative multi-attribute reverse auctions in practice create certain difficulties for both the buyer and participating bidders. While the buyer faces the problem of creating the right attribute weights, the bidders have difficulty in adjusting the attribute values in each round. In this paper, we present an iterative multi-attribute reverse auction mechanism based on integrated data envelopment analysis (DEA) and best–worst method (BWM) with an objective of reducing the intervention of the buyer in the determination of the winner and also easing up the preference elicitation process. Unlike the typical scoring auctions, the proposed mechanism does not require the buyer to estimate the characteristics of the participating sellers in order to determine the optimal scoring function. As there will be no other intervention from the buyer during the winner determination process, the proposed method makes the procurement process impartial and corruption-free. Besides solving the buyer’s problem, the proposed mechanism is also associated with an optimal bid determination method (OBDM) to assist the sellers in formulating improvised bids in iterative rounds of the auction. Simulation experiments show that the proposed OBDM benefits both the buyer and sellers. For the buyer, it provides higher expected utility and attribute values as per his preferences; for the seller, it gives a better expected profit and a higher probability of winning.

Framework for Deterministic Assessment of Risk-Averse Participation in Local Flexibility Markets †

Local flexibility markets (LFMs) are a market-based concept to integrate distributed energy resources into congestion management. However, the activation of flexibility for storage-based flexibility changes the respective state of charge. Compensation in later points of time is needed to regain the original flexibility potential. Therefore, we propose a LFM bid formulation including both flexibility and compensation. Furthermore, flexibility market participation might lead to inc-dec-gaming, i.e., congestion-increasing behavior to maximize profits. However, this inc-dec-gaming might lead to electricity market schedule deviations if LFM offers are not activated. We propose a risk-averse modeling formulation considering the potential non-activation of LFM bids to provide a framework for the assessment of LFM participation comparing different approaches. Our exemplary case studies demonstrate the proposed LFM bid formulation and show the impact of LFM participation modeling on inc-dec-gaming and congestion management costs.

ADMM-based market clearing and optimal flexibility bidding of distribution-level flexibility market for day-ahead congestion management of distribution networks

Nowadays, the massive deployment of distributed energy resources in distribution networks poses more operational challenges such as network congestion to distribution system operators. To cope with these challenges in an economically efficient way, the distribution system operator can utilize demand-side flexibility traded in the local flexibility market to manage the distribution network. In the existing distribution-level flexibility market frameworks, the market operator is assumed to have access to network parameters in order to ensure the market clearing solution being technically feasible from the operational point of view. To protect the privacy of network parameters, this paper proposes an alternating direction method of multipliers -based market clearing strategy, in which the market operator communicates with the distribution system operator to clear the market such that the market clearing solution respects network operation constraints without revealing network parameters to the market operator. In addition, in the existing flexibility bid formulations, the energy payback condition is determined without considering operation constraints of flexibility resources and the flexibility cost has not been considered. To fill this gap, this paper formulates an optimal flexibility bidding model for aggregators, which carefully models the energy payback condition and enables the aggregator to receive the maximum revenue with flexibility costs considered. The case studies were conducted on the Roy Billinton Test System with electrical vehicles and heat pumps as flexibility resources. The results demonstrate that the proposed distribution-level flexibility market framework is effective to perform day-ahead congestion management of distribution networks and is profitable to aggregators and end-users.

Implementation of Reactive Power Markets to Enhance the Power System Network.

Reactive power is an important component which plays a critical role in maintaining grid reliability, especially voltage stability. The report presents an analysis of the current compensation strategies followed by different independent system operators (ISOs) in US and identifies the drawbacks in the present compensation schemes. The properties of reactive power which poses an impediment to setup a reactive power market has been compared with the need of a reactive power market. Finally, a possible spot market structure has been considered along with bid formulation and its different components as applicable to different reactive power producing equipment.

Energy-intense production-inventory planning with participation in sequential energy markets

To support the uprise of demand response, especially in the context of industrial processes, we propose a new approach to integrally determine the production-inventory plan and the cost-minimizing bids to participate in sequential reserve and energy-only markets. In particular, our approach considers time-coupling constraints which occur in the context of a production-inventory planning problem. We extend this problem with a comprehensive bidding formulation, which allows evaluating revenues and potential cost from the market participation, considering price uncertainties and uncertain activations of committed reserve capacity. This results in a multistage stochastic mixed-integer linear program, which explicitly considers the stage-wise revelation of information in our setup. To illustrate the capabilities of our approach, we apply our model to a real-world case study in which we investigate the participation of a cement plant in the German energy-only and reserve markets. The results of our case study indicate significant revenues for flexible industrial processes when participating in German spot and reserve markets.

Impact of Load Profile on Dynamic Interactions Between Energy Markets: A Case Study of Power Exchange and Demand Response Exchange

Demand response exchange (DRX) presents a pool-based approach for optimal clearing/scheduling of demand response (DR) services through bid clearing. The same is intended to minimize the limitations of price-based and incentive-based mechanisms. However, unlike the price-based or incentive-based DR schemes, the DR sellers in DRX do not have a clear motivation to formulate the bid offers. Similarly, the DR buyers’ bid formulation should also include optimal benefit analysis. This paper formulates and analyzes the bid formulation for DR sellers and buyers considering respective operation objectives. The DR seller bid formulation is derived considering load behavior through utilization index and availability index obtained from load profile of respective loads. On the other hand, DR buyer bid formulation is derived from power exchange operation attributes/cost of generation. Therefore, the DR clearing ultimately affects the operational cost of operation which, in turn, is reflected in DR buying bid and DR clearing finally. This paper develops an iterative approach in which the continuous interactions between ISO/power exchange would finally converge to a stable operation. The load profile-based strategic bid formulation is modeled using mathematical as well as fuzzy inference system (FIS). In addition, an adaptive FIS has been devised to improve the performance of DR scheduling. The simulation results illustrate the impact of customer behavior, intelligent decision-making, and penetration level on the performance and convergence of power markets (DRX and power exchange).

Optimal Market Participation of Distributed Load Resources Under Distribution Network Operational Limits and Renewable Generation Uncertainties

Distributed load resources are encouraged nowadays to actively participate in the energy market. As a part of the distribution system, they affect the power flow pattern of the network and interact with intermittent renewable generation in the distribution system. In this regard, one fundamental challenge, not yet addressed, is to derive an optimal market participation model, under the demand bidding paradigm, that systemically accounts for the operational limits of a physical distribution grid considering uncertainty associated with both the electricity market , and distribution network system . Accordingly, this paper addresses the optimal demand biding under uncertain market and distribution system data and network operational limits. Assuming a price-taker distribution utility with renewable energy, inflexible and deferrable loads and a two-settlement market model, we develop a two-stage robust stochastic bidding formulation solved using a decomposition algorithm. We derive optimal bid curves that minimize energy procurement cost and fully comply with the operational standards of the distribution network. Moreover, novel indexes are proposed to help the utility evaluate the operational performance of its network with regard to deferrable loads and renewable resources. Finally, we illustrate the advantage of the proposed model from a set of numerical experiments on an example system and the 33-bus system.

A Comparative Study of Once Daily Versus Twice Daily Tacrolimus in Liver Transplantation

Background: Once daily (OD) tacrolimus, recently launched for post liver transplant immunosuppression might offer better compliance and efficacy compared to standard twice daily (BID) tacrolimus. Data from India, however is sparse. Aim: The aim of our study was to compare the efficacy and adverse effects of OD versus BID tacrolimus formulation in liver transplant recipients. Methods: This was a retrospective, observational, comparative study of 115 patients who were on tacrolimus based regimens (tacrolimus BID: 92; M: F-75:17 and tacrolimus OD: 23; M: F-22:1). Total daily dose and trough levels of tacrolimus were recorded at 1, 3, 6, 12 and 24 months after transplantation. Results: Median age in tacrolimus BID and OD groups were 45 years (6-64 years) and 50 years (1-70 years), respectively. The median tacrolimus dose was significantly lower in the tacrolimus OD arm at all the time points studied. Tacrolimus trough levels were significantly lower in the tacrolimus OD group at 3 and 6 months. The biopsy proven rejection rate was 15.2% and 0% in the tacrolimus BID and OD groups, respectively. Two year patient and graft survival rate was 89.4% in the tacrolimus BID and 87.5% in the tacrolimus OD group. The incidence of new onset diabetes, renal dysfunction, dyslipidemia, neurotoxicity, hyperkalemia and weight gain were comparable between the two arms. Conclusion: Tacrolimus OD has a lower rejection rate compared to its BID formulation. However, this does not translate into better patient or graft survival. Both the formulations appear to be comparable with respect to the adverse effect and tolerability profile. Key words: Biopsy Proven Acute Rejection, Graft Survival, Patient Survival, Liver Transplantation, Tacrolimus Once Daily, Tacrolimus Twice Daily.

Risk-Averse Optimal Bidding Strategy for Demand-Side Resource Aggregators in Day-Ahead Electricity Markets Under Uncertainty

This paper first presents a generic model to characterize a variety of flexible demand-side resources (e.g., plug-in electric vehicles and distributed generation). Key sources of uncertainty affecting the modeling results are identified and are characterized via multiple stochastic scenarios. We then propose a risk-averse optimal bidding formulation for the resource aggregator at the demand side based on the conditional value-at-risk (VaR) theory. Specifically, this strategy seeks to minimize the expected regret value over a subset of worst-case scenarios whose collective probability is no more than a threshold value. Our approach ensures the robustness of the day-ahead (DA) bidding strategy while considering the uncertainties associated with the renewable generation, real-time price, and electricity demand. We carry out numerical simulations against three benchmark bidding strategies, including a VaR-based approach and a traditional scenario based stochastic programming approach. We find that the proposed strategy outperforms the benchmark strategies in terms of hedging high regret risks, and results in computational efficiency and DA bidding costs that are comparable to the benchmarks.

Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet

PurposeLorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration–approved, extended-release, 20-mg once-daily formulation. MethodsWe performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. FindingsCompared with lorcaserin IR, the Tmax after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the Cmax was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, Tmax after a single dose was identical (median, 12 hours), but Cmax was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, Cmax and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations. ImplicationsOverall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation.

Pharmacokinetic Study of Conversion from Tacrolimus Twice-Daily to Tacrolimus Once-Daily in Stable Lung Transplantation

Tacrolimus twice-daily (TAC BID) is widely used in lung transplantation (LT), but there are little data on the use of tacrolimus once-daily (TAC QD) in this population. The objective of this study was to compare the pharmacokinetics (PK) of TAC BID and TAC QD in stable, adult LT patients. Phase II, open-label, single-center, single-arm, prospective pilot PK study. Nineteen LT recipients with more than 6 months of postoperative follow-up and on TAC BID-based therapy were converted to TAC QD on a 1:1 (mg/mg) basis. Patients had been stable during the previous 3 months, and cystic fibrosis patients were excluded. One 24-hr PK profile was obtained on day -14 while patients were under TAC BID. A second PK profile was obtained 14 to 28 days after switching (day 0) to the same dose of TAC QD. Pre- and post-switch 24-hr PK profiles were compared. Mean AUC0-24 hr was 279.8 ng mL/hr for TAC BID and 278.7 ng mL/hr for TAC QD (P=0.92). AUC0-12 hr of TAC BID was higher than the AUC12-24 hr. There was a good correlation between AUC0-24 hr and C24 for both QD (r=0.96) and BID (r=0.94) formulations. There were no differences in the adverse events occurring with the two formulations. Tacrolimus bioavailability in steady state is similar in BID and QD formulations after conversion in stable LT recipients, excluding those with cystic fibrosis. Thus, our results indicate TAC BID can be safely switched to the more convenient QD formulation in this population.

Abstract 148: Association of Dosing Frequency on Medication Adherence in Patients with Non-Valvular Atrial Fibrillation

Objective: Previous studies suggest that the complexity of a dosing regimen may affect medication adherence. We examined the association between dosing frequency and adherence for 2 concomitant medications commonly prescribed to patients with non-valvular atrial fibrillation (NVAF), metoprolol (MET) and carvedilol (CAR). Methods: A retrospective claims study from a large US commercial and Medicare Advantage health plan analyzed data of adults ( &gt; 18 years) with 1 inpatient or 2 outpatient claims for NVAF between 1/1/2008 - 12/31/2010. Patients with &gt; 2 pharmacy claims for MET or CAR were analyzed separately. Within MET and CAR samples, once-daily (QD) and twice-daily (BID) cohorts were defined by the dosing frequency on pharmacy claims. The index date was set as the date of the first MET or CAR claim. Patients were continuously enrolled in the health plan for 1 year before (pre-index) and 1 year after (post-index) the index date. MET patients were required to have &gt; 1 pre-index claim for acute myocardial infarction, angina, heart failure, or hypertension; CAR patients were required to have ≥1 claim for heart failure or hypertension. Patients using both QD and BID formulations of the index medication were excluded. Adherence to the index medication was assessed by the proportion of days covered (PDC) during the post-index period. PDC between QD and BID patients was compared using logistic regression to adjust for demographic and pre-index clinical characteristics. The proportion of QD and BID patients who discontinued the index medication (defined by a gap &gt; 30 days) during the post-index period was also compared. Results: The analysis included 11,621 MET patients (QD: 6,084; BID: 5,537) and 4,393 CAR patients (QD: 203; BID: 4,190). Mean (SD) age was 70 (12) years for MET and CAR patients; 59% of MET and 69% of CAR patients were male. Compared to patients with BID dosing, patients with QD dosing were on average younger, more likely to be male, and had a lower comorbidity burden. Fewer patients discontinued MET or CAR with QD than BID dosing (MET: 38% vs. 51%, p&lt;0.001; CAR: 39% vs. 48%, p=0.009). The proportion of patients with PDC &gt; 80% was greater for patients with QD than BID dosing (MET: 62% vs. 50%, p&lt; 0.001; CAR: 63% vs. 53%, p=0.004). MET patients with BID dosing were less likely to achieve PDC &gt; 80% than patients with QD dosing (adjusted OR: 0.66; 95% CI: 0.609-0.712). CAR patients with BID dosing were less likely to achieve PDC &gt; 80% than patients with QD dosing (adjusted OR: 0.69; 95% CI: 0.508-0.934). Among MET and CAR patients, age &lt;60 years was associated with lower adherence (p&lt;0.001) while prior use of index medication was associated with higher adherence (p≤0.001) to the index medication. Conclusion: Medication adherence to MET and CAR was higher with QD than BID dosing. Quality initiatives that reduce the dosing frequency of treatment regimens may improve medication adherence among NVAF patients.

Conversion from twice daily tacrolimus to once daily tacrolimus in long-term stable liver transplant recipients: A single-center experience with 394 patients

After organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The aim of the present study was to evaluate the safety and efficacy of conversion from a tacrolimus (TAC) twice daily (bid) formulation to a once daily (qd) formulation in a large cohort of adult liver transplantation (LT) patients. This retrospective, observational, single-center study included 394 LT patients with at least 6 months' posttransplant follow-up and no rejection episodes in the last 3 months. The conversion from a bid formulation to a qd formulation was based on a 1:1 ratio. The mean age at the time of conversion was 53 years (range = 18-72 years); 66% were men. The main indication for LT was alcoholic cirrhosis (41%). The mean conversion time after LT was 74 months (range = 6-218 months). The mean serum TAC trough level decreased after conversion (6.1 ± 5.6 ng/mL before conversion versus 4.9 ± 2.5 ng/mL after conversion, P < 0.05). After a mean follow-up of 24 months after conversion, 6 patients had converted to cyclosporine, 14 patients had stopped all calcineurin inhibitors, 16 patients had returned to TAC bid, and 358 patients were still on TAC qd. Acute rejection episodes were observed in 7 patients. In conclusion, the results of our experience indicate that the conversion from a TAC bid formulation to a qd formulation is a safe and effective strategy for the management of stable LT patients.

Once– versus twice–daily tacrolimus: are the formulations equivalent?

Tacrolimus is one of the most often used immunosuppressive drugs in organ transplantation. It was first approved in 1994 for use in liver transplantation, replacing cyclosporine A, due to better absorption properties regardless of bile secretion. Then it use was extended to other organs and nowadays more that 90% of kidney graft recipient in the United States receive tacrolimus as a basic immunosuppressant [1]. The use of tacrolimus is complicated by its narrow therapeutic index and wide intra– and interpatient pharmacokinetics variability, thus it dosage should be based on monitoring trough drug blood concentration. The main complications of drug overdosage are nephro– and neurotoxicity and metabolic disturbances like posttransplant diabetes mellitus and hyperlipidemia. On the other hand low, non–therapeutic drug blood level can lead to graft rejection and loss. Patients’ noncompliance is the main cause of fluctuating tacrolimus blood concentration and in many cases could be the reason of acute graft rejection episodes. It is an important problem both in young, active but also in older kidney graft recipients and reduction of immunosuppressive drugs daily doses is one method to overcome this problem [2]. The once–daily (OD) extended–release formulation of tacrolimus (Advagraf, Astellas) was launched in 2007 in 0.5, 1, 3, and 5 mg doses. This drug formulation allows most of liver transplant and some kidney transplant recipients (on tacrolimus monotherapy or in dual therapy with prednisone) to use only one morning dose of immunosuppressants. Such therapy simplifies treatment protocol and increases patient compliance. Converting patients from twice daily (BID) to OD tacrolimus was proposed on equivalent daily dose but there was a concern of adequate blood levels after treatment switch. We observed in our center that OD tacrolimus doses had to be 10–15% higher than BID formulation to get the same trough blood drug concentration after conversion. In a multicenter, open–label, phase III study in stable adult liver transplant recipients converted from tacrolimus BID to OD (1:1 [mg:mg] total daily dose basis). Following conversion, mean tacrolimus trough levels were reduced by approximately 15% (7.5 ng/ml vs. 6.5 ng/ml; P <0.0001) but were more consistent, showing reduction between– and within–patient variability in trough levels [3]. However, in our retrospective analysis of 60 kidney graft recipients converted from tacrolimus BID to OD formulation in identical (1:1) daily doses in late posttransplant period trough blood drug concentration did not significantly differ pre and after conversion. OD tacrolimus doses were increased in 11 patients and decreased in 13 patients based on trough blood concentration during consecutive patient visits (unpublished data). OD tacrolimus is non inferior to BID formulation in long term effect in kidney transplant recipients. A systematic review of 6 randomized controlled trials and 15 observational studies revealed no significant differences in biopsy–proven acute rejection, patient and graft survival between the two formulations at 12 months [4]. However, there are some disadvantages of OD tacrolimus therapy. First, risk of overdose–related side effects is very high in first postransplant days and with BID tacrolimus formulation dose correction can be made with the evening dose. Secondly, only 1 mg OD tacrolimus capsules are reimbursed in Poland, making treatment rather difficult in case of higher daily doses. In the present paper authors describe their experience with kidney transplant recipients from living donors who received OD tacrolimus [5]. They investigated tacrolimus pharmacokinetics and compared the dose of OD tacrolimus OD TAC to BD drug formulation. The study group is relatively small and there are some demographic differences between the groups that could affect pharmacokinetic parameters of the study drug: patients on OD tacrolimus were younger and were shorter time on dialysis. The authors compare daily doses and minimal concentration (Cmin) of both formulations, what is most important in clinical practice. However, detailed pharmacokinetic parameters are presented only for OD tacrolimus. In conclusions OD tacrolimus appears to have efficacy and safety equivalent to that of BD formulation but a larger dose of OD tacrolimus compared to that of BD drug form may be required during the early period after kidney transplantation [5].

Optimal Combined Bidding of Vehicle-to-Grid Ancillary Services

Vehicle-to-grid (V2G) has the potential of reducing the cost of owning and operating electric vehicles (EVs) while increasing utility system flexibility. Unidirectional V2G is a logical first step because it can be implemented on standard J1772 chargers and it does not degrade EV batteries from cycling. In this work an optimal combined bidding formulation for regulation and spinning reserves is developed to be used by aggregators. This formulation takes into account unplanned departures by EV owners during contract periods and compensates accordingly. Optional load level and price constraints are also developed. These algorithms maximize profits to the aggregator while increasing the benefits the customers and utility. Simulations over a three month period on the ERCOT system show that implementation of these algorithms can provide significant benefits to customers, utilities, and aggregators. Comparisons with bidirectional V2G show that while the benefits of unidirectional V2G are significantly lower, so are the risks.

An auction-based strategy for distributed task allocation in wireless sensor networks

Game theory provides a mathematical tool for the analysis of distributed decision making interactions between agents with conflicting interests. We apply game theory for distributed task allocation in wireless sensor networks (WSNs) where the decision makers in the game are the sensor nodes willing to perform the task to maximize their profits. They have to cope with limited resources (i.e., available energy levels) that imposes a conflict of interest. In resource-constrained wireless sensor networks, one of the fundamental challenges is to achieve a fair energy balance among nodes to maximize the overall network lifetime. Auction-based schemes, owing to their perceived fairness and allocation efficiency, are among the well-known game theoretic mechanisms for energy balanced distributed task allocation. In this paper, the real-time distributed task allocation problem is formulated as an incomplete information, incentive compatible and economically-robust reverse auction game. The main objective of this scheme is to maximize the overall network lifetime considering the application’s deadline as the constraint. In the proposed game theoretic model, the distributed best response for bid updates globally converges to the unique Nash Equilibrium in a completely asynchronous manner. Another problem addressed in this paper is the winner determination problem. Given a distributed pool of bids from bidders (i.e., sensor nodes), a centralized winner determination protocol (WDP) would require costly message exchanges with high energy consumption and overhead. Hence, we propose the Energy and Delay Efficient Distributed Winner Determination Protocol (ED-WDP) for the reverse auction-based scheme. Our simulation results show a fairer energy balance achieved through this bid formulation in comparison to other well-known static schemes. Moreover, by utilizing the ED-WDP among the numerous distributed resources, the message exchange overhead, energy consumption and delay for winner determination are significantly reduced compared to a centralized WDP.