Pharmacotherapy of Paget's disease of bone

Introduction: Paget's disease of the bone is a common condition in some populations, affecting almost 10% of older adults in western Europe. Though frequently asymptomatic, it can sometimes result in severe disabilities. Timely intervention is now able to arrest disease progression in the majority of patients.

Areas covered: Studies describing the pharmacotherapy of Paget's disease are described in this review, based on a weekly Current Contents search for the term ‘Paget’ from 1995, and from personal knowledge and published references from earlier literature.

Expert opinion: Potent bisphosphonates are the cornerstone of current therapy and have been shown to produce biochemical remission, radiographic healing, pain relief and an improved quality of life. A single intravenous dose of zoledronate has produced the highest response rates and the most sustained remissions of any medication studied so far. It is not clear whether Paget's disease is cured in these patients, or whether they merely undergo a prolonged remission. As a result of this approach, we seldom need to retreat patients and our clinical experience is entirely consonant with the long-term follow-up results from the zoledronate trials, indicating that this treatment results in better clinical outcomes and greater quality of life for patients with Paget's disease.     

Long dosing intervals in the treatment of postmenopausal osteoporosis

ABSTRACT

Background: Osteoporosis is a common disease associ­ated with diminished bone strength and increased risk of fracture. With the aging of the population, the number of people with osteoporosis, particularly postmenopausal women, is expected to increase. There are excellent tools for diagnosing osteoporosis and widely available treat­ments that are safe and effective. Nevertheless, osteo­porosis is underdiagnosed and undertreated. Even among those who are diagnosed and treated, widespread non­adherence with treatment regimens undermines the efficacy of osteoporosis therapy.

Purpose: To examine the pharmacological options for the treatment of postmenopausal osteoporosis and the influence of extended dosing intervals upon outcomes, medication adherence, and patient preference.

Methods: A Medline and Cochrane Review database search was conducted for appropriate clinical trials, meta-analyses, and systematic reviews published between 1987 and 2007.

Findings: The causes of nonadherence include poor understanding of the consequences of a silent disease, concern regarding potential side-effects of medications, the inconvenience associated with administration of some osteoporosis medications, and medication costs. The recent development of effective oral and injectable osteo­porosis medications that can be given with long dosing intervals may improve patient adherence. Less frequent dosing lessens the inconvenience of administration, and dosing by injection assures that the medication is 100% bioavailable. Osteoporosis patients have shown a preference for monthly bisphosphonate dosing compared with weekly dosing.

Conclusion: Enhanced adherence with new dosing regimens can be expected to improve treatment efficacy, reduce fracture risk, and lessen the burden of osteo­porosis on patients and society. Further study is required to fully elucidate the relationship between extended dosing, adherence, and positive outcomes.     

Dickkopf-1 as a potential therapeutic target in Paget's disease of bone

Importance of the field: Wnt signalling plays a role in maintaining healthy bone mass. Dickkopf-1 (DKK-1) is a soluble inhibitor of Wnt signalling and its excessive expression contributes to bone loss in rheumatoid arthritis and multiple myeloma. New therapeutics have been developed for treatment of these conditions that target DKK-1 expression. DKK-1 is elevated in serum of patients with Paget's disease of the bone (PDB) and evidence is accumulating for a role of DKK-1 in PDB.

Areas covered in this review: The role of Wnt signalling and DKK-1 in bone health and disease and the aetiology of PDB in the light of recent advances in understanding of Wnt signalling.

What the reader will gain: PDB is a disorder of unknown aetiology characterised by localised increase in unregulated bone remodelling resulting in osteolytic and osteosclerotic lesions. Evidence is adduced for the involvement of Wnt signalling, DKK-1 and osteoblasts in PDB pathogenesis.

Take home message: At present there is no cure for PDB and the current treatment of choice are bisphosphonates. These treat the resorptive phase of PDB but do not prevent its return. We present a new perspective on the aetiology of PDB and speculate on DKK-1 as a therapeutic target.     

The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives

Importance of the field: Breast cancer is one of the leading causes of cancer-related deaths in the world. Despite the significant improvements in the adjuvant treatment strategies of early-stage breast cancer, many patients experience relapse. Bisphosphonates are widely used in the treatment of bone metastasis of solid tumors and multiple myeloma, as well as in osteoporosis. The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanisms and antitumoral activity of bisphosphonates.

Areas covered in this review: The current literature on the preclinical and clinical studies into antitumoral effect and adjuvant treatment of bisphosphonates, especially zoledronic acid, are summarized. Data in the literature over the last two decades were also reviewed.

What the reader will gain: The reader will find a summary of preclinical and clinical studies of antitumoral effect and adjuvant treatment with bisphosphonates, in particular zoledronic acid, as well as ongoing trials about adjuvant treatment of breast cancer with zoledronic acid and ibandronate.

Take home message: Current evidence supports zoledronic acid as an effective treatment in adjuvant breast-cancer therapy for hormone-receptor-positive breast-cancer patients when added to hormonotherapy. Uncertainty about effects of zoledronic acid and other bisphosphonates will be clarified after completion of ongoing trials.     

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma

SUMMARY

Objective: Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit.

Data sources: Published articles and data on file (Novartis PharmaAG, Genentech).

Results: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50ng/ml (20.8?IU?ml^?1) or less (target 25?ng?ml^?1 (10.4IU?ml^?1)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient's

weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150–375?mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators.

Conclusions: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.     

An audit to determine the time taken to administer intravenous bisphosphonate infusions in patients diagnosed with metastatic breast cancer to bone in a hospital setting

ABSTRACT

Objective: Bone metastases can occur in many forms of cancer. More than two-thirds of women with metastatic breast cancer may be affected by bone metastasis during the course of their disease. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are an established standard of care for patients with bone metastases. For patients with cancer and bone metastases, bisphosphonates are associated with a significant reduction in skeletal-related events such as vertebral fractures, non-vertebral fractures as well as increasing the time to skeletal event. The purpose of this study was to quantify the current time involved in the administration of IV bisphosphonates and how this might impact on patient experience and cancer unit capacity.

Research design and methods: A pilot audit was initially conducted at the Royal Marsden Hospital (RMH), London (both Chelsea and Sutton sites), and was followed by audits at a further two UK hospital sites: Velindre Hospital, Cardiff and the Royal Surrey County Hospital, Guildford. The study was conducted between December 2005 and September 2006.

Results: Overall, 151 forms were completed. Of the total patients audited, approximately 71% had a diagnosis of breast cancer. Where data on the reason for attendance were collected (Velindre and the Royal Surrey County Hospital), over 77% of patients attended hospital for the sole reason of having an IV bisphosphonate administered. The majority of patients (94%) required cannulation prior to infusion and, at the sites where this information was recorded (Royal Surrey County Hospital and Velindre Hospital), almost one-third of patients required two or more attempts before they were successfully cannulated. The time that the patients spent on the unit where the IV bisphosphonates were administered was greater for patients receiving pamidronate compared to those receiving zoledronic acid (2?h 36?min and 1?h 38?min, respectively). The magnitude of the difference was not as great as would be expected considering zoledronic acid should take one-sixth of the time to administer (Royal Marsden Hospital, pamidronate 1?h 29?min, zoledronic acid 18 min: Royal Surrey County Hospital, zoledronic acid 21 min: Velindre Hospital, pamidronate 1?h 42?min, zoledronic acid 17?min).

Conclusions: IV bisphosphonates are accepted as standard clinical practice for the management of metastatic bone disease. They are often prescribed for long periods of time, so tolerability and patient acceptability are important factors in therapy. The administration of IV bisphosphonates contributes a substantial time burden for patients travelling to the hospital, considering that in most cases the purpose is for this treatment only. It also places a significant burden on hospital resources, creating capacity planning challenges. Receiving an IV bisphosphonate also has other disadvantages associated with it, such as the need for patients to undergo repeated cannulation. Service redesign, such as home administration of IV bisphosphonates, could help to overcome issues highlighted in this audit. The use of oral alternatives to pamidronate and zoledronic acid which may be more convenient for patients, and perhaps also cost-effective, should also be of ongoing interest.     

Zoledronic acid for treatment of Paget's disease of bone

Paget's disease of bone is characterised by a focal increase in bone resorption and bone formation. This anarchic metabolism leads to disorganised bone, with bone pain, fragility, deformity and compression of the peripheral or CNS according to the involved site. Quality of life of sufferers is dramatically impaired. Symptomatic therapy trends to relieve pain, but cannot seek to prevent other complications. Only ‘specific’ therapy can fulfil this purpose. Bisphosphonates have become the cornerstone for therapy of Paget's disease in the last 25 years. Progressively stronger bisphosphonates have been launched on the market. The last drug available, zoledronic acid, the most potent of this drug family, can be administered intravenously. It possesses a long-acting efficacy, allowing a follow up on a yearly basis and permitting the chance of a very long remission of the Pagetic lesion. In the long term, prevention of severe complications can be envisaged, with a reasonable pharmacoeconomic cost.     

Correlation between zoledronic acid infusion and repeat vertebroplasty surgery in osteoporotic patients

Objective The incidence of bone fractures rapidly increases as people age, mostly due to bone loss resulting from osteoporosis. The purpose of this study is to compare the rates of repeat vertebroplasty in osteoporotic patients treated with or without zoledronic acid (ZOL) infusion following initial vertebroplasty.

Research design and methods We conducted a retrospective chart review of osteoporotic patients who underwent vertebroplasty from June 2009 to June 2012. Patients with existing vertebral fracture(s) were retrospectively divided into two groups according to whether or not they received zoledronic acid infusion after initial vertebroplasty. Zoledronic acid infusion was intravenously administered once a year for three consecutive years, as a single 5?mg dose in 100?mL solution infused over at least 15?minutes. The primary efficacy variable was the number of patients requiring repeat vertebroplasty procedures after the initial surgery due to subsequent vertebral fractures. The Cox proportional hazards model was used to compare the risk ratios of repeat vertebroplasty between these two groups.

Results A total of 1646 patients, including 456 males and 1190 females (age range: 65–89 years), were enrolled. Compared to the 1595 patients who did not receive osteoporosis medication, the 51 patients treated with zoledronic acid infusion demonstrated a significantly lower rate of repeat vertebroplasty. In the ZOL-treated group, only 4% of the patients (2/51) required a second vertebroplasty, compared to 13% (206/1595) in the non-ZOL-treated group (p?=?0.032).

Conclusions The results indicate that osteoporotic patients who undergo vertebroplasty are significantly less likely to require reoperation if treated with zoledronic acid infusion. However, since the number of male patients in the ZOL-treated group was limited, and since Taiwan’s National Health System program does not cover the cost of receiving zoledronic acid infusions for male patients, the conclusion seems to be less certain for male osteoporotic patients.     

Zoledronic acid

Importance of the field: Both bone metastases and fragility fractures due to bone loss result in considerable morbidity affecting quality of life and independence as well as placing complex demands on healthcare resources. Zoledronic acid is a widely used intravenous bisphosphonate that reduces this skeletal morbidity in both benign and malignant conditions.

Area covered in this review: The incidence, clinical importance and prevention strategies to minimize side effects associated with the use of zoledronic acid are discussed with a particular focus on use in oncology where intensive monthly scheduling is required. This potentially increases the risk for adverse events over the 6 – 12 monthly administration used to treat benign bone diseases.

What the reader will gain: A detailed understanding of the generally favorable safety profile of zoledronic acid, but particularly the potential for renal dysfunction and osteonecrosis of the jaw.

Take home message: When compared to many other therapies, especially in the cancer setting, the severity of adverse events related to zoledronic acid is generally mild and, with the exception of the acute phase response causing transient fever, myalgia and bone pain, side effects are infrequent. Thus, the benefits of treatment with zoledronic acid within its licensed indications almost always outweigh the risks.     

Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch

Abstract

1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson’s disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration.

2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1?mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5?mg (2 and 4?cm²) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t_1/2), time to peak plasma-concentration (T_max), mean residence time (MRT), area under the curve (AUC_(0–t)) were significantly (p?<?0.05) different between transdermal and oral administrations.

3. The plasma half-life (t_1/2) of rasagiline (1.25?mg patch: 11.8?±?6.5?h, 2.5?mg patch: 12.5?±?4.7?h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1?mg tablet: 4.7?±?2.5?h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5?mg patches compared with 1?mg rasagiline tablet. The prolonged t_1/2 and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet.     

Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis

SUMMARY

Objective: The efficacy and tolerability of risedronate once-a-week dosing (35 and 50?mg) were compared with risedronate daily dosing (5?mg) in a 2-year study in women with osteoporosis.

Design and methods: This was a randomized, double-blind, active-control study with lumbar spine bone mineral density (BMD) as the primary efficacy endpoint at 1?year. Subjects were women aged 50?years or older, postmenopausal for at least 5?years, and had either a BMD T-score of –2.5 or lower (lumbar spine or total proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. In addition to risedronate treatment, the subjects received 1000?mg daily of elemental calcium supplementation and received vitamin D if the baseline serum 25-hydroxyvitamin D₃ level was low.

Results: The results after 1?year of treatment were previously published. Of the 1456 women who were randomized and received study medication, 1127 (77%) completed the 2-year study. Over the 2?years of treatment, the incidence of both new vertebral fractures (2.9, 1.5, and 1.7% for the 5, 35, and 50?mg groups, respectively; p = 0.298) and osteoporosis-related non-vertebral fractures reported as adverse events (5.0, 4.9, and 4.5% for the 5, 35, and 50?mg groups, respectively; p = 0.918) was similar for all 3 treatment groups. The reduction from baseline at Month 24 in bone turnover markers was similar based on an analysis of variance for the 5?mg daily and the 35?mg once-a-week groups. The mean percentage change in lumbar spine BMD after 24?months was 5.17, 4.74, and 5.47% for the 5, 35, and 50?mg groups, respectively. Both the 35 and 50?mg once-a-week treatment groups met the pre-specified criterion of non-inferiority to the 5?mg daily treatment group. No apparent difference in the pattern or distribution of serious and upper gastrointestinal adverse events was observed.

Conclusions: The 2-year data agree with the 1-year results demonstrating that the risedronate once-a-week doses are comparable in efficacy and safety to the 5?mg daily dose. Risedronate 35?mg once a week is considered the optimal dose for women with postmenopausal osteoporosis who want a once-a-week dosing regimen.     

Costs and consequences of using pamidronate compared with zoledronic acid in the management of breast cancer patients in the UK

ABSTRACT

Objective: To estimate the costs and consequences of using pamidronate compared to zoledronic acid in the prophylactic management of skeletal morbidity among breast cancer patients in the UK.

Design and setting: This was a modelling study performed from the perspective of the UK's National Health Service (NHS).

Methods: Published clinical outcomes from a comparative study were combined with resource utilisation estimates derived from a panel of clinicians. This enabled the construction of a decision model depicting the management of patients with breast cancer receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed). There are no significant differences in outcome between using pamidronate and zoledronic acid in breast cancer patients. Therefore, a cost minimisation analysis was performed to identify the treatment strategy that achieves the same outcome for least cost. The expected time attributable to a pamidronate and zoledronic acid infusion was also estimated.

Main outcome measures and results: Starting treatment with pamidronate among patients receiving chemotherapy is expected to lead to a healthcare cost of £6046 over 12 months compared to £6981 with zoledronic acid. In comparison, for patients receiving hormonal therapy, starting treatment with pamidronate is expected to lead to a healthcare cost of £5401 over 12 months compared to £6043 with zoledronic acid. This cost difference is primarily due to the lower acquisition cost of pamidronate and fewer tests among pamidronate-treated patients. Accordingly, pamidronate affords a less expensive management modality. Multivariate analysis showed the expected time attributable to a pamidronate infusion to be 110 to 277 minutes compared with 136 to 296 minutes for a zoledronic acid infusion.

Conclusion: Use of pamidronate instead of zoledronic acid affords an economic benefit to the NHS. Moreover, published clinical trials show no statistical difference between pamidronate and zoledronic acid at 1 year. Hence, within the limitations of our model and the published evidence, pamidronate is the preferred first-line intravenous bisphosphonate for use in breast cancer patients receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed).     

Osteoclast differentiation inhibitors: a patent review (2008 – 2012)

Introduction: Mononuclear macrophage/monocyte-lineage hematopoietic precursors differentiate into multinucleated osteoclasts. Abnormally increased numbers and/or overactivation of osteoclasts can lead to bone loss. Therefore, pharmaceutical inhibition of osteoclast differentiation is one therapeutic strategy for mitigating the occurrence of bone loss-associated disorders and related fractures.

Areas covered: This review surveys the patents and patent applications from 2008 to 2012 that are related to inventions of therapeutics and/or methods for inhibiting osteoclast differentiation.

Expert opinion: Over the past 20 years, the identification and validation of signaling molecules involved in osteoclast differentiation has led to a better understanding of the molecular mechanism, and to the development of new therapeutic agents for treating bone loss-associated disorders. Since 2008, 34 WO patents or patent applications have been filed that relate to inventions of therapeutics and/or methods for chemical-based, natural product-based, or biological-based inhibitors of osteoclast differentiation. Here, analysis of these patents and patent applications is presented, and summarize the disclosed osteoclast differentiation-inhibiting target molecules. This report can support further advances in the development of anti-osteoclastogenic therapeutics for bone loss-associated disorders, including osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, osteosarcoma, and cancer bone metastasis.     

Treatment with alendronate plus calcium,alendronate alone,or calcium alone for postmenopausal low bone mineral density

ABSTRACT

Objective: Bisphosphonates such as alendronate are widely used for postmenopausal osteoporosis. Supplemental calcium is also generally recommended. This trial directly compares alendronate to supplemental calcium and examines the effect of calcium supplementa­tion on alendronate treatment.

Methods: This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake ≥?800?mg/day received daily vitamin D 400?IU and alendronate 10?mg/calcium-placebo, alendronate 10?mg/elemental calcium 1000?mg, or alendronate-placebo/calcium 1000?mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events.

Results: Randomized patients (N = 701) were an average of 20.4 years postmenopausal. After 24 months, increases in lumbar spine BMD differed significantly between patients receiving calcium alone (0.8%) and either alendronate alone (5.6%) or alendronate + calcium (6.0%) (?p < 0.001). Significant differences were also seen at the trochanter and femoral neck (?p < 0.001). BTMs were significantly lower with alendronate-containing treatments than calcium alone (?p < 0.001). Addition of calcium supplementation to alendronate did not signif­icantly increase BMD compared to alendronate alone (?p = 0.29 to 0.97), but did result in a statistically significant, though small, additional reduction in urinary NTx. Adverse events were similar among treatment groups. Limitations include no assessment of vitamin D levels and a discontinuation rate of approximately 30%, although discontinuation rates were similar among treatment groups.

Conclusions: In postmenopausal women with a daily intake of ≥?800?mg calcium and 400?IU vitamin D, 24-month treatment with alendronate 10?mg daily with or without calcium 1000?mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment had no effect on BMD and resulted in a small, though statistically significant, additional reduction in NTx.     

The potential role for cladribine in the treatment of multiple sclerosis: clinical experience and development of an oral tablet formulation

ABSTRACT

Background: Disease-modifying drugs available for multiple sclerosis (MS) require chronic, regular, parenteral administration. Effective oral MS therapies may improve long-term adherence. A number of oral therapies are in development, including cladribine – a preferential lympho­cyte-depleting therapy with a well-established safety profile across other indications.

Objective: To review information available on the safety and efficacy of cladribine in the treatment of MS, in the context of the ongoing development of an oral tablet formulation.

Methods: An electronic search was performed to identify publications in which ‘cladribine’ was listed as a major index term. Results of the literature search were supplemented by other relevant secondary references and publications.

Findings: The majority of published data on cladribine describe its use in diseases other than MS. However, three major, industry-sponsored, double-blind, placebo-controlled trials of parenteral cladribine were identified, involving 262 patients with relapsing or progressive forms of MS. Patients received cumulative doses of 0.7–2.8?mg/kg of cladribine over 4–6 months and were followed-up for at least 6–12 months thereafter.

Individual results of these studies of parenteral cladribine indicate that it can reduce: (i) the number and volume of T1 gadolinium-enhancing lesions; (ii) the accumulation of T2 lesion volume; (iii) relapse rate; and (iv) disability progression. A dose-dependent increase in adverse events was observed, leading to selection of low doses for use in an ongoing clinical development program of an oral tablet formulation. Efficacy and safety data from four independent studies/case reports have also supported the potential benefits of cladribine in MS.

Conclusion: Preliminary data indicate that cladribine is effective for the treatment of MS and has a promising safety and tolerability profile. The sustained immunologic effects of cladribine make it suitable for intermittent oral dosing, which is expected to offer benefits for patient satisfaction and therapeutic adherence.     

Single-dose and steady-state bioequivalence of fexofenadine and pseudoephedrine combination tablets compared with individual formulations in healthy adults

ABSTRACT

Objective: A 24-h extended-release formulation of fexofenadine HCl 180?mg/pseudoephedrine HCl 240?mg (FEX 180?mg/PSE 240?mg) has recently been approved by the US Food and Drug Administration for symptom relief of seasonal allergic rhinitis, including nasal congestion. When considering a combination formulation, it is important to confirm that the metabolism and pharmacokinetics of the drugs remain unchanged when combined. Thus, the aim of this study was to evaluate single-dose and steady-state bioequivalence of FEX 180?mg/PSE 240?mg 24-h compared with the individual formulations taken concurrently.

Research design and methods: This was an open-label, randomized, two-treatment, two-period, 10-day, crossover study. In Treatment A, healthy subjects received a single, oral dose of FEX 180?mg/PSE 240?mg combination tablet on Day 1 followed by 6 days of once-daily dosing beginning on Day 4. Participants in Treatment B were concurrently administered a single oral dose of FEX 180?mg immediate-release tablet and a PSE 240?mg extended-release tablet with a similar dosing schedule. After an 8-day washout period, subjects crossed over to the alternate treatment. Plasma concentrations of FEX and PSE were determined using high-performance liquid chromatography/mass spectrometry.

Results: Pharmacokinetic parameters AUC(0?∞)₁ and C_max1 following a single-dose (Day 1, dose 1), C_max7, AUC(0?24)₇ at steady-state and C_min7 measured at the end of the dosing interval (Day 9, dose 7) revealed bioequivalence between FEX 180?mg/PSE 240?mg combination tablet and the individual components taken concurrently. The 90% confidence intervals for the treatment ratios fell entirely within the bioequivalence range (80% to 125%). The combination tablet was well tolerated by all subjects, with a safety profile comparable to the individual components.

Conclusions: These findings demonstrate that the pharmacokinetics of the new 24-h FEX 180?mg/PSE 240?mg combination formulation are bioequivalent to the concurrent administration of the individual drug components. Furthermore, both treatments were well tolerated in this population.     

Memantine ER,a once-daily formulation for the treatment of Alzheimer's disease

Importance of the field: Alzheimer's disease is a progressive, degenerative brain disease. As the disease progresses, patients and caregivers face increasing problems with medication adherence. Given its relentlessly progressive nature, newer and more effective therapies for Alzheimer's disease are needed. Memantine 10 mg twice daily is the FDA-approved regimen for the treatment of moderate to severe Alzheimer's disease.

Areas covered in this review: The goal of this article is to review the once-daily memantine ER 28 mg formulation for the treatment of Alzheimer's disease, which, by simplifying the dosage regimen, decreases the problems of medication adherence. A new extended-release formulation has been developed to improve adherence and possibly efficacy without compromising an excellent tolerability and safety profile. There is also a possibility of dose-dependent improvement/superiority in cognitive, global and behavioral measures as well as in verbal fluency with higher-dose (28 mg/day) memantine.

What the reader will gain: Readers will become knowledgeable about this new dose and preparation of memantine. However, these advantages remain provisional and more research is needed to evaluate patient adherence, outcomes and caregiver burden related to twice-daily versus once-daily administration in patients with moderate to severe Alzheimer's disease.

Take home message: A new, once-daily, higher-dose preparation of memantine seems to be well tolerated and may provide additional benefits for selected patients with Alzheimer's disease.     

Rivastigmine exposure provided by a transdermal patch versus capsules

ABSTRACT

Objectives: The rivastigmine transdermal patch is the first transdermal treatment for Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The objective of this study was to evaluate the pharmacokinetics of rivastigmine following transdermal delivery by a patch versus oral delivery with conventional capsules in a population of AD patients.

Methods: Both non-compartmental and compartmental analyses were performed on the same database showing relatively large inter-patient variations in pharmacokinetic parameters (up to 73% for the capsule group). The compartmental analysis provided model-based predictions of pharmacokinetic parameters, with the aim of comparing the two modes of administration when adjusting for confounding factors such as patient body weight and gender.

Results: According to both non-compartmental and compartmental analyses, the patch provided significantly lower peak rivastigmine plasma concentrations (C_max) and slower times to C_max (t_max), compared with capsules. However, drug exposure (area under the curve; AUC) was not significantly different between the 4.6?mg/24 hour (5?cm²) patch and 3?mg BID (6?mg/day) capsule doses, or between the 9.5?mg/24 hour (10?cm²) patch and 6?mg BID (12?mg/day) capsule doses, according to both analyses. This suggests comparable exposure from these two rivastigmine delivery systems.

Conclusion: The analyses were consistent with previous reports of a markedly less fluctuating, more continuous drug delivery with the rivastigmine patch. This characteristic delivery profile is associated with similar efficacy yet improved tolerability, compared with capsules.     

Ibandronate produces significant,similar antifracture efficacy in North American and European women: new clinical findings from BONE

ABSTRACT

Objectives: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2?months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here.

Patients and methods: BONE was a randomized, double-blind, placebo-controlled, fracture-prevention study in 2946 postmenopausal women (age 55?years?80?years; ≥ 5?years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4?L4]). Participants received daily calcium (500?mg) and vitamin D (400?IU) plus either placebo, oral daily ibandronate (2.5?mg) or oral intermittent ibandronate (20?mg every other day for 12 doses every 3?months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations.

Results: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (?p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo.

Conclusions: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients’ geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.