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- Letter in Response to the Review by De Maria et al. 2014
- Foster®: A High-Efficiency Combination Metered Dose Inhaler with
Consistent Particle Size Distribution at Alternative Flow Rates
Abstract: Introduction This publication adds perspective to a recent publication by Johal et al. that presented the performance of combination inhalation therapies at a flow rate differing from that recommended by the regulatory authorities for metered dose inhaler (MDI) performance testing. Altering the flow rate through an impactor can create potential pitfalls which can result in performance misrepresentation. Performance Testing of MDIs at Non-Standard Flow Rates In-house data for Foster® (Chiesi, Parma, Italy) and Flutiform® (Bard Pharmaceuticals Limited, Cambridge, UK) have been collected using standard pharmacopaeial conditions and also at the unconventional 60 L/min flow rate utilized by Johal et al. A marked reduction in mass median aerodynamic diameters (MMADs) of both the inhaled corticosteroids (ICS) and long-acting beta agonists in Foster MDI from approximately 1.2–0.5 μm with increase in flow rate (Johal et al.) is not observed. Use of the Andersen cascade impactor at flow rates above 28.3 L/min is not common practice. The industry generally utilizes data from the next generation impactor (NGI), an impactor specifically designed and developed for this purpose. Data for the ICS component of Foster have been generated using an NGI operated at 30 and 60 L/min, yielding an MMAD (±SD) of 1.1 ± 0.1 μm at both flow rates. Therapeutic Significance of Submicron Particles Johal et al. suggest that submicron particles are prone to be exhaled by the patient, and therefore imply that they may be non-effective. However, therapeutic significance of submicron particles is supported by a scintigraphic lung deposition study carried out using the Foster MDI. The in vivo data highlight that just 2–3% of the nominal dose was exhaled, with 31–34% deposited in the lungs. Conclusion Consistent particle size distribution of both active drug components delivered from Foster MDI at flow rates of 28–30 and 60 L/min is observed.
PubDate: 2014-01-03
- Evolution of Coronary Stents: From Bare-Metal Stents to Fully
Biodegradable, Drug-Eluting Stents
Abstract: Abstract Coronary stenting represents the standard of care for percutaneous revascularization of symptomatic coronary artery disease. However, despite progress in the evolution of intravascular stents, clinical adverse events such as restenosis and stent thrombosis still represent the “achilles heel” of this ground-breaking technology. Of particular note was the association of these adverse events with the material, the polymer coating, and the active drug of currently approved drug eluting stents. Consequently, modifications were made to the design, coating, and the choice of drugs, eventually, resulting in (fully) biodegradable drug-eluting stents. Such stents offer the appealing concept of a temporary vascular scaffold and are currently under extensive preclinical and clinical investigation. However, biodegradable stents must demonstrate efficacy and safety in larger randomized clinical trials in real-world scenarios, which are currently on the horizon.
PubDate: 2013-12-11
- Fine Particle Profile of Fluticasone Propionate/Formoterol Fumarate Versus
Other Combination Products: the DIFFUSE Study
Abstract: Introduction The efficacy of inhaled products is affected by the degree, and potentially the site, of drug particle deposition in the lungs. Lung deposition correlates with the fine particle fraction (FPF; the proportion of dose containing particles <5 μm in aerodynamic diameter). This in vitro study (defining fluticasone propionate/formoterol particulate size [DIFFUSE]) examined the effects of inhalation flow rate on the FPF of the fluticasone propionate/formoterol (FP/FORM) pMDI aerosol compared with three other inhaled corticosteroids/long-acting β2-agonist (ICS/LABA) combination therapies administered by either DPI or pMDI [fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (BUD/FORM) and beclometasone dipropionate/formoterol (BDP/FORM)]. Methods Aerodynamic particle size distribution was determined for each product using an 8-stage Andersen Cascade Impactor at two inhalation flow rates: 28.3 and 60.0 L/min. Fine particle dose (mass of dose <5.0 μm) and FPF were calculated as a percentage of the labeled dose for the LABA and ICS of each product at both flow rates. Results FP/FORM suspension aerosol provided a high and consistent FPF of approximately 40% for the ICS and LABA components at both flow rates. At 28.3 L/min, the FPF of each component of FP/FORM (41.2% and 39.2%) was greater than that of FP/SAL DPI (12.5% and 11.3%), BUD/FORM DPI (8.2% and 6.6%) and BDP/FORM pMDI (28.5% and 26.0%). At 60.0 L/min, the FPFs of the FP/FORM components (43.7% and 42.1%) were greater than those of FP/SAL (17.8% and 14.8%) and BUD/FORM (35.0% and 30.1%), and similar to those of BDP/FORM (43.0% and 39.5%). Discussion The FP/FORM suspension aerosol produced a high and consistent FPF of approximately 40% across both flow rates. The consistent FPF in vitro may be predictive of FP/FORM providing more consistent drug dosing in vivo, helping to counteract variable lung dose due to variation in inspiratory flow rate among patients and between a patient’s day-to-day or successive inhalation maneuvers.
PubDate: 2013-08-30
- Combination of Cytotoxic Drugs for Patients with HER2-Negative Metastatic
Breast Cancer
Abstract: Abstract In the last few decades the approach to metastatic breast cancer (MBC) treatment using chemotherapy, either as single or combination agents, has been largely studied and a wide spectrum of therapeutic options is now available. Anthracyclines and taxanes remain the cornerstone of treatment in this setting. The choice of combination chemotherapy versus monochemotherapy is still open to debate since results from clinical trials are, unfortunately, conflicting. Despite improvements in response and disease-free survival rates, there has been no overall survival benefit reported although toxicity is increased. Therefore, based on available data, clinical decision-making for a busy practitioner should consider not only patient/tumor characteristics and the potential benefits of treatments, but also their toxicity profiles and patient preferences. Novel cytotoxic compounds have been approved for clinical use and combination regimens incorporating these agents may bring new treatment opportunities for MBC patients. In this review, we summarize the main achievements and the currently available and future combinations of cytotoxic drugs for patients with HER2-negative MBC.
PubDate: 2013-08-28
- Abatacept and Mycophenolate Mofetil Combination Therapy in Refractory
Pediatric Systemic Lupus Erythematosus: A Case Series
Abstract: Introduction Lupus nephritis (LN) in pediatric systemic lupus erythematosus (pSLE) requires treatment with corticosteroids (CS) and mycophenolate mofetil (MMF) or cyclophosphamide (CYC). However, some patients fail standard therapy leaving physicians with few options. Although two recent phase II/III randomized controlled trials using abatacept (ABA) with and without MMF in adult SLE did not meet their endpoints, we examined if this combination therapy may have a therapeutic benefit in pSLE patients with refractory class IV and V LN. Methods We performed a retrospective chart analysis of five pSLE patients with class IV and V LN. All patients were treated with ABA + MMF after previous failure to CYC and MMF. CS doses and SLE Disease Activity Index (SLEDAI) score were assessed at diagnosis and after 12 and 24 weeks of each treatment. Results Patient age at diagnosis was 9–15 years (mean 12.6 ± 2.3). Average disease duration before initiation of ABA + MMF therapy was 22–97 months (mo) (mean 52.8 ± 30.8). Treatment with ABA + MMF resulted in an improvement in SLEDAI score and reduction in CS dose by 12 weeks in all five patients. One patient achieved complete remission and three patients were weaned off steroids after 7–20 mo (mean 13 ± 6.5). Repeated measures analysis of variance showed significant change from SLEDAI at time of diagnosis (baseline) over 24 weeks of treatment with CYC (P = 0.0013) and with ABA + MMF (P < 0.0001). Paired comparison to baseline SLEDAI scores showed some decrease after 12 weeks of treatment with MMF monotherapy (P = 0.0520). Conclusion The data suggest that combination therapy with ABA + MMF may be an alternative option in refractory pSLE nephritis. Additional studies are needed in pSLE to further assess the efficacy of this combination treatment.
PubDate: 2013-08-08
- Stribild, a Single Tablet Regimen for the Treatment of HIV Disease
Abstract: Introduction In August 2012, the US Food and Drug Administration (FDA) approved a new single tablet once-a-day therapy for treatment-naïve HIV patients. The new tablet contains emtricitabine and tenofovir disoproxil fumarate as well as elvitegravir and cobicistat, a pharmacokinetic enhancer which prolongs the effect of elvitegravir. The new tablet (EVG/COBI/FTC/TDF), known as Stribild® (Gilead Sciences, Foster City, CA, USA), is now the only FDA-approved single-tablet, once-daily, HIV medication that is composed of an integrase-inhibitor-based regimen. Methods Stribild has been tested in two randomized double-blind phase 3 clinical trials with 1,408 patients who had not been previously treated for HIV. In one trial, Stribild was compared to the single-tablet regimen gold standard medication known as Atripla® (Gilead Sciences, Foster City, CA, USA) that contains efavirenz, emtricitabine and tenofovir disoproxil fumarate (EFV/FTC/TDF). In the second clinical trial, Stribild was compared to another preferred treatment regimen of ritonavir-boosted atazanavir (ATV/RTV) with coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF, marketed as Truvada®; Gilead Sciences, Foster City, CA, USA). Results The outcomes of the two recently published trials at 48 weeks indicated that Stribild was noninferior to both of the standard treatment regimens in controlling viral load. In the Stribild versus Atripla trial, 305 of 348 patients (87.6%) on Stribild versus 296 of 352 patients (84.1%) on Atripla had an HIV ribonucleic acid (RNA) concentration of <50 copies/mL at week 48. In the Stribild versus ATV/RTV with Truvada trial, 316 of 353 patients (89.5%) on Stribild versus 308 of 355 patients (86.8%) on Atripla had an HIV RNA concentration of <50 copies/mL at 48 weeks. Conclusion Stribild had a favorable safety profile in the two recently published randomized, double-blind, phase 3 clinical trials. With the approval of Stribild, clinicians now have more flexibility in prescribing single-tablet regimens for patients.
PubDate: 2013-03-26
- A Review of the Combination of Phentermine and Topiramate Extended-Release
for Weight Loss
Abstract: Abstract The Food and Drug Administration recently approved the combination of phentermine and extended-release topiramate (PHN/TPM) for weight loss. This is one of only two weight-loss agents to arrive on the US market in the last decade. This product combines the anorexigenic agent, phentermine, which is approved for the short-term treatment of weight loss, with a carbonic anhydrase inhibitor, topiramate, which is approved for non-weight loss indications, including seizure disorders and migraine headache. Although the combination is believed to be synergistic, no clinical trial data currently address this. The PHN/TPM combination is a once-daily formulation. Mean weight loss among participants who completed 1 year of PHN/TPM treatment in research trials, in combination with lifestyle modification, has ranged from approximately 7% (lower doses) to over 14% (higher doses), relative to approximately 2% with placebo. In addition to weight loss, PHN/TPM resulted in improved comorbidities and quality of life, although it has not been shown to improve mental/psychosocial issues. Among the common adverse events observed in clinical trials are paresthesia, dry mouth, constipation, and headache. Other noteworthy adverse events that occurred more commonly with PHN/TPM versus placebo included dysgeusia, insomnia, irritability, and alopecia. Laboratory abnormalities in serum bicarbonate and potassium were also observed in a subset of patients. Due to the teratogenic potential of topiramate, women of child-bearing potential are required to have a negative pregnancy test at baseline and are instructed to take monthly pregnancy tests. As part of a risk-management approach, only pharmacies certified by the manufacturer will be allowed to dispense PHN/TPM and will be required to provide information on birth defects. Like phentermine, the combination drug will be designated as a schedule IV medication. In comparison with other agents currently on the market, the combination of PHN/TPM appears to provide significant advantages for weight loss, while improving comorbid conditions and quality of life. Monitoring for laboratory abnormalities, adverse events, and changes in psychiatric status should occur during therapy.
PubDate: 2012-10-24
- Alogliptin-Pioglitazone Combination Therapy: A Rational Approach to
Treating Type 2 Diabetes Mellitus
Abstract: Abstract Introduction: Type 2 diabetes mellitus (T2DM) is a complex disease with a number of metabolic abnormalities. At present, treatment typically proceeds in a stepwise fashion, beginning with diet and exercise followed by incremental additions of oral antidiabetic agents as required to achieve and maintain glycemic control (glycosylated hemoglobin [HbA1c] ≤6.9% and 6.5%, respectively). This approach is reactive rather than proactive as progression to the next level is based on treatment failure (i.e., not achieving target HbA1c levels). Newer approaches to treatment of T2DM advocate early use of combination antihyperglycemic regimens with complementary mechanisms of action to correct multiple pathophysiologic defects, but this can impact negatively on treatment adherence. Fixed-dose combinations are associated with higher compliance rates than therapy with individual components administered concomitantly. This review examines evidence for a fixed-dose combination of alogliptin and pioglitazone recently approved for use in Japanese patients with T2DM. Methods: A MEDLINE search identified five randomized, controlled trials in which alogliptin and pioglitazone were used in combination to treat T2DM, and these form the basis of the review. Results: One study evaluated alogliptin-pioglitazone combination therapy in drug-naïve patients. In the remaining studies, alogliptin was evaluated as add-on therapy in patients with inadequate glycemic control despite treatment with pioglitazone (± metformin or sulfonylurea). In all studies, alogliptin-pioglitazone combination therapy consistently produced statistically significant reductions in HbA1c of approximately 0.6–1.0% over and above those produced by either agent alone. This improvement was paralleled by improvements in fasting plasma glucose, proportions of patients achieving target HbA1c levels and several other measures of glycemic control, including markers of beta-cell function. The alogliptin-pioglitazone combination was well tolerated across all studies. Conclusion: Alogliptin-pioglitazone combination therapy represents a rational approach to treatment of T2DM as the complementary mechanisms target several aspects of impaired glucose control. The fixed-dose combination offers scope for enhanced patient compliance and improved treatment outcomes.
PubDate: 2012-10-03
- Unique Risks, Benefits, and Challenges of Developing Drug-Drug Combination
Products in a Pharmaceutical Industrial Setting
Abstract: Abstract Treatment with a single drug targeting a specific receptor is no longer considered optimal in the treatment and management of complex diseases such as HIV/AIDS, diabetes, and cardiovascular disease. Potential health benefits may arise from the use of affordable, multiple-target, fixedratio drug combinations, which concomitantly reduce multiple risk factors without increasing the risk of adverse effects. Main goals for development of fixed-dose drug combinations may largely be based on the following concepts: treatment of two closely related diseases (e.g., hyperlipidemia and hypertension), patients insufficiently controlled by optimally dosed individual monotherapies, and substitution of fixed-dose combination versus free combination. Success in creating and developing the bestin- class commercial combination products requires a multifaceted approach including the following: 1) treatment paradigms in therapeutic area; 2) patient compliance and impact of personalized medicine; 3) shifts in market and cost drivers; 4) preclinical and pharmaceutical development and manufacturing; 5) competitive intellectual property landscape; and 6) clinical development and regulatory filing strategy. Assessment of risks and probability of success of specific drug combinations and drug delivery technologies are needed in order to arrive at the proper recommendation and risk mitigation plans. Personalization of combination therapy is rationalized on the theoretical premise of division of clinical responders from partial or nonresponders to drugs in diseases for which known biomarkers exists. Combination drug therapies with individualized optimization are likely to become a major future focus. A comprehensive review of industrial practice and literature is presented with the goal of developing a best practices roadmap in the feasibility assessment of drug combination therapies.
PubDate: 2012-03-29
- Medications Used for Acne Vulgaris: Practice Trends and the Use of Topical
Combination Products
Abstract: Introduction Acne is a common disease caused by multiple factors affecting the pilosebaceous follicles. As a result of the multifactorial nature of this disease, current treatment guidelines recommend using drugs from multiple classes. Adherence is a challenge when multiple drugs are needed in a treatment regimen. Newer combination products may help physicians combat this issue. The purpose of this paper was to examine prescribing patterns in the treatment of acne focusing on combination-product use. Methods The National Ambulatory Medical Care Survey database was queried for visits for acne. Visits were analyzed for patient demographics and treatment regimens. Prescription for common treatments and combination products were analyzed to determine changes in prescribing over time. Results The most common treatment for acne was topical retinoids. Two combination products were within the top 10 acne treatments. The use of combination products is increasing in primary care specialties (1.26% per year; P=0.002) as well as among dermatologists (0.66% per year; P<0.001). Primary care physicians (12.6%) prescribed combination products at a higher percentage of visits than did dermatologists (11.5%). Conclusion The use of combination acne products is increasing. The use of combination products is expected to increase as a means of reducing treatment complexity and increasing adherence to treatment.
PubDate: 2012-02-02
- Combination Cytotoxic and Antiangiogenic Therapy in the Management of
Epithelial Ovarian Cancer
Abstract: Abstract The majority of patients with advanced epithelial ovarian cancer respond to primary platinum/taxane-based combination chemotherapy. Unfortunately, recurrence is the rule rather than the exception in this clinical setting. In addition, multiple trials focused on the addition of a “third” cytotoxic drug to a platinum/taxane combination have failed to demonstrate any improvement in outcome. However, recent data reveal that addition of the antiangiogenic agent, bevacizumab, to either a primary platinum-based chemotherapy program or platinumbased therapy to manage recurrent disease can substantially improve time to subsequent disease progression and potentially favorably affect overall survival. This review discusses the rationale supporting the combination of cytotoxic and antiangiogenic therapy in advanced epithelial ovarian cancer, the existing evidence-based data supporting this strategy, and possible future research directions in this difficult malignancy.
PubDate: 2012-01-11
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