Nitric Oxide Releasing Nanoparticles as a Strategy to Improve Current Onychomycosis Treatments.

Topical antimicrobials are the ideal mode of onychomycosis treatment for efficient drug delivery and avoidance of sytemic effects associated with oral medications. However, high treatment costs, tissue penetration limitations, and low cure rates have continued to pose major challenges. To capitalize on the progress made by topical efinaconazole solution, efinaconazole was combined with inexpensive, previously-characterized nitric oxide releasing nanoparticles (NO-np), which have been shown to offer sustained nitric oxide release over time and enhanced barrier penetration, while exerting broad spectrum antimicrobial and immunomodulating properties. NO-np were combined with efinaconazole in varying concentrations and applied against reference strains of Trichophyton rubrum using a checkerboard method. Results demonstrated synergism of NO-np+efinaconazole against T. rubrum, which is noteworthy given the barriers present in the topical treatment of onychomycosis, and the multiple potential benefits offered by NO-np. Overall, this study illustrates the untapped potential of nanotechnology in the treatment of disorders of the skin, hair, and nails where drug delivery remains a challenge. J Drugs Dermatol. 2018;17(7):717-720.

Cost effectiveness of paricalcitol versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients in the USA.

BACKGROUND: The IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism] study compared the effectiveness of paricalcitol and cinacalcet in the management of secondary hyperparathyroidism in haemodialysis patients but did not report the costs or cost effectiveness of these treatments. AIM: The aim of this study was to compare the cost effectiveness of a paricalcitol-based regimen versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients from a US payer perspective, using a 1-year time horizon. METHODS: This was a post hoc cost-effectiveness analysis of data collected for US patients enrolled in the IMPACT SHPT study-a 28-week, randomized, open-label, phase 4, multinational study (ClinicalTrials.gov identifier: NCT00977080). Patients eligible for the IMPACT SHPT study were aged≥18 years with stage 5 chronic kidney disease, had been receiving maintenance haemodialysis three times weekly for at least 3 months before screening and were to continue haemodialysis during the study. Only US patients who reached the evaluation period (weeks 21-28) were included in this secondary analysis. US subjects in the IMPACT SHPT study were randomly assigned to receive intravenous paricalcitol, or oral cinacalcet plus fixed-dose intravenous doxercalciferol, for 28 weeks. Patients in the paricalcitol group could also receive supplemental cinacalcet for hypercalcaemia. The primary effectiveness endpoint in the IMPACT SHPT study was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) level of 150-300 pg/mL during the evaluation period. In this secondary analysis, we estimated the incremental cost-effectiveness ratio (ICER), comparing paricalcitol-treated patients with cinacalcet-treated patients on the basis of this primary endpoint and several secondary endpoints. Costs were estimated by examining the dosage of the study drug (paricalcitol or cinacalcet) and phosphate binders used by each participant during the trial. Nonparametric bootstrap analysis was used to examine the accuracy of the ICER point estimates. RESULTS: The percentages of patients achieving the treatment goal of a mean iPTH level between 150-300 pg/mL during weeks 21-28 of therapy were 56.9% in the paricalcitol group and 34.0% in the cinacalcet group (a difference of 23%, p=0.0235). Paricalcitol was also more effective for each of the secondary endpoints. When annualized, the total drug costs were US$10,153 in the paricalcitol group and US$15,967 in the cinacalcet group, a difference of US$5,814 (57.3%, p=0.0053). Because the paricalcitol-based treatment was less expensive and more effective, it was 'dominant', compared with cinacalcet, in this cost-effectiveness analyses. In our bootstrap analysis, 99.1% of bootstrap replicates for the ICER of the primary endpoint fell within the lower right quadrant of the cost-effectiveness plane-where paricalcitol is considered dominant. For all of the other endpoints, paricalcitol was dominant in 100% of replicates. CONCLUSION: On the basis of dosing and effectiveness data from US patients in the IMPACT SHPT study, we found that a regimen of intravenous paricalcitol was more cost effective than cinacalcet plus low-dose vitamin D in the management of iPTH in patients with SHPT requiring haemodialysis.

Cinacalcet: a pharmacoeconomic review of its use in secondary hyperparathyroidism in end-stage renal disease.

This article provides an overview of the clinical profile of the calcimimetic agent cinacalcet (Mimpara®, Sensipar®) in the treatment of patients with secondary hyperparathyroidism (SHPT) undergoing dialysis for end-stage renal disease (ESRD), followed by a comprehensive review of pharmacoeconomic analyses with cinacalcet in this patient population. Most patients with ESRD undergoing dialysis develop SHPT, which is associated with disturbances in bone mineral metabolism and the development of fractures, cardiovascular disease and other clinical events. Standard treatment of SHPT includes phosphate binders and active vitamin D derivatives. However, standard treatment alone seldom achieves recommended target plasma or serum levels of parathyroid hormone (PTH), calcium and phosphorous. The addition of cinacalcet to standard therapy in patients with SHPT undergoing dialysis for ESRD improves the likelihood of achieving target biochemical levels compared with standard therapy alone. On the basis of association studies, improvements in these intermediate endpoints are likely to reduce the risk of clinical events, such as fractures and cardiovascular disease. Therefore, part of the acquisition cost of cinacalcet is likely to be offset by reductions in other healthcare resource use, such as reductions in costs associated with a lower likelihood of clinical events, as well as potential reductions in dosages of standard treatment. A number of pharmacoeconomic analyses across various country settings indicate that cinacalcet plus standard therapy is cost effective relative to standard therapy alone if dialysis costs are excluded, or that early initiation of cinacalcet is cost effective compared with delaying cinacalcet treatment until PTH levels become very uncontrolled. However, across analyses with cinacalcet, results were variable and not always favourable. This wide range of results stems from differences in selection of data sources used to populate the models, regional differences in healthcare resource use and costs, as well as other factors. Future cost-effectiveness analyses with cinacalcet should incorporate data on hard clinical outcomes from the EVOLVE study once this information becomes available.

Economic evaluation of cinacalcet in the treatment of secondary hyperparathyroidism in Italy.

BACKGROUND: Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. METHODS: We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range [TiR]) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. RESULTS: Baseline results were calculated with 10,000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was €50,012 per LY and €67,361 per QALY, while, if dialysis costs were not included, the ICER was €23,473 per LY and €31,616 per QALY. CONCLUSIONS: The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.

Economic analysis of cinacalcet in combination with low-dose vitamin D versus flexible-dose vitamin D in treating secondary hyperparathyroidism in hemodialysis patients.

BACKGROUND: The ACHIEVE (Optimizing the Treatment of Secondary Hyperparathyroidism: A Comparison of Sensipar and Low Dose Vitamin D vs Escalating Doses of Vitamin D Alone) trial evaluated the efficacy of treatment with cinacalcet plus low-dose activated vitamin D analogues (Cinacalcet-D) compared with vitamin D analogues alone (Flex-D) in attaining KDOQI (Kidney Disease Outcomes Quality Initiative) targets for secondary hyperparathyroidism (SHPT). The economic implications of these treatment regimens have not been explored. STUDY DESIGN: Economic analysis of SHPT treatment in hemodialysis patients. SETTING & POPULATION: This analysis used data from the ACHIEVE trial, in which patients received either Cinacalcet-D or Flex-D. MODEL, PERSPECTIVE, & TIME FRAME: We assessed the relative cost-effectiveness of these regimens in treating SHPT during the 27-week ACHIEVE trial, using a US payer perspective, with medication costs valued in 2006 US dollars. INTERVENTION & OUTCOMES: Relative cost-effectiveness was assessed using cost-minimization analysis or incremental cost-effectiveness ratios. Effectiveness was measured using biochemical markers. RESULTS: Mean medication costs per patient were $5,852 and $4,332 for the Cinacalcet-D and Flex-D treatment arms, respectively. There were no significant differences for the primary end point (parathyroid hormone level of 150-300 pg/mL and calcium-phosphorus product < 55 mg²/dL²) and several of the secondary end points, rendering Cinacalcet-D more costly than Flex-D. For secondary end points, for which Cinacalcet-D was more effective, incremental cost-effectiveness ratios ranged from $2,957 (calcium < 9.5 mg/dL) to $22,028 (all KDOQI targets) per patient reaching target. Switching to generic calcitriol would have increased the cost difference between treatment arms ($2,079), whereas switching sevelamer to lanthanum decreased the difference ($1,426). LIMITATIONS: Costs and outcomes were derived from a short-term randomized controlled trial and were protocol driven. Clinical outcomes, such as mortality, were not available. Long-term economic conclusions cannot be drawn from these data. CONCLUSIONS: Cinacalcet combined with vitamin D analogues was no more effective than vitamin D analogues in achieving the primary ACHIEVE end point and incurred greater costs. This conclusion was not tempered substantially by the cost of vitamin D analogues or oral phosphate binders. Whether the additional costs of cinacalcet are warranted will require longer term models to determine whether changes in serum levels of mineral metabolic markers translate into lower morbidity, mortality, and downstream costs.

A cost analysis of topical drug regimens for dermatophyte infections.

OBJECTIVE: To examine the extra cost of using higher-priced drugs as initial therapy for dermatophyte infections, because the many available effective drugs vary considerably in cost. DESIGN: Cost analysis from the purchaser's perspective, comparing two prototypical regimens to treat tinea pedis: one in which all patients initially receive a lower-priced drug and those with unresponsive infections receive a higher-priced drug at a follow-up office visit, and one in which all patients receive the higher-priced drug from the outset. The reference drug was miconazole, an imidazole available without a prescription, for which reported overall efficacy rates are 70% to 100%. MAIN OUTCOME MEASURES: The threshold efficacy rate (the efficacy rate of miconazole below which it is always less expensive to use a specific higher-priced drug first) and the extra cost (of beginning therapy with a higher-priced drug). RESULTS: Assuming the Medicare-approved charge for a follow-up visit ($21.98), it is less expensive to begin therapy with a prescription drug only if the efficacy rate of miconazole is less than 55%; this threshold efficacy rate varied from 26% (for a $0 total cost of the follow-up visit) to 79% (for an $89 total cost of the follow-up visit). If the efficacy rate of miconazole is 70%, the extra cost per patient for all patients to receive the least expensive prescription antifungal drug instead of miconazole first was $15.23 and $8.64 if total visit costs were $0 and $21.98; miconazole remained the less expensive alternative as long as the total cost of the follow-up visit was less than $50.76. CONCLUSION: For reported efficacy rates and standard costs of a follow-up office visit, using miconazole first and then treating only those patients with unresponsive infections with a higher-priced prescription drug is less expensive than treating all patients with the higher-priced drug.