Update on the Safety and Bioequivalence of Biosimilars – Focus on Enoxaparin.

Update on the safety and bioequivalence of biosimilars – focus on enoxaparin.

Drug Healthc Patient Saf. 2013; 5: 133-141
Jeske W, Walenga JM, Hoppensteadt D, Fareed J

Generic forms of chemically-derived drugs must exhibit chemical identity and be bioequivalent in healthy human subjects. The use of generic drugs results in a considerable savings of healthcare expenditures. Biologic drugs are produced in living systems or are derived from biologic material and extend beyond proteins to include antibodies, polysaccharides, polynucleotides, and live viral material. Such drugs pose a challenge to characterize as they tend to be larger in size than chemically-derived drugs, can exhibit a variety of post-translational modifications, and can have activities that are dependent on specific conformations. Biosimilars are not true generics, but rather, exhibit a high degree of similarity to the reference product and are considered to be biologically and clinically comparable to the innovator product. Therefore, the development process for biosimilars is more complex than for a true generic. Guidance is now available from the US Food and Drug Administration and from the European Medicines Agency for the development of biosimilar drugs. Biosimilar drugs are expected to have a major impact in the management of various diseases in coming years. HubMed – drug


A biodegradable polymeric system for peptide-protein delivery assembled with porous microspheres and nanoparticles, using an adsorption/infiltration process.

Int J Nanomedicine. 2013; 8: 2141-2151
Alcalá-Alcalá S, Urbán-Morlán Z, Aguilar-Rosas I, Quintanar-Guerrero D

A biodegradable polymeric system is proposed for formulating peptides and proteins. The systems were assembled through the adsorption of biodegradable polymeric nanoparticles onto porous, biodegradable microspheres by an adsorption/infiltration process with the use of an immersion method. The peptide drug is not involved in the manufacturing of the nanoparticles or in obtaining the microspheres; thus, contact with the organic solvent, interfaces, and shear forces required for the process are prevented during drug loading. Leuprolide acetate was used as the model peptide, and poly(d,l-lactide-co-glycolide) (PLGA) was used as the biodegradable polymer. Leuprolide was adsorbed onto different amounts of PLGA nanoparticles (25 mg/mL, 50 mg/mL, 75 mg/mL, and 100 mg/mL) in a first stage; then, these were infiltrated into porous PLGA microspheres (100 mg) by dipping the structures into a microsphere suspension. In this way, the leuprolide was adsorbed onto both surfaces (ie, nanoparticles and microspheres). Scanning electron microscopy studies revealed the formation of a nanoparticle film on the porous microsphere surface that becomes more continuous as the amount of infiltrated nanoparticles increases. The adsorption efficiency and release rate are dependent on the amount of adsorbed nanoparticles. As expected, a greater adsorption efficiency (~95%) and a slower release rate were seen (~20% of released leuprolide in 12 hours) when a larger amount of nanoparticles was adsorbed (100 mg/mL of nanoparticles). Leuprolide acetate begins to be released immediately when there are no infiltrated nanoparticles, and 90% of the peptide is released in the first 12 hours. In contrast, the systems assembled in this study released less than 44% of the loaded drug during the same period of time. The observed release profiles denoted a Fickian diffusion that fit Higuchi’s model (t(1/2)). The manufacturing process presented here may be useful as a potential alternative for formulating injectable depots for sensitive hydrophilic drugs such as peptides and proteins, among others. HubMed – drug


Tivozanib in the treatment of renal cell carcinoma.

Biologics. 2013; 7: 139-148
Hepgur M, Sadeghi S, Dorff TB, Quinn DI

Renal cell carcinoma (RCC) is an aggressive malignancy compared to other urological malignancies and has been associated with poor responses to conventional cytotoxic chemotherapy. Interferon-? and interleukin-2 were previously utilized in a limited number of patients with good performance status due to toxicity and safety issues. Over the last decade, through advances in the understanding of the biology and pathology of RCC, the important role of vascular endothelial growth factor (VEGF) in RCC has been identified. Data from randomized trials have led to the approval of first-generation tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib; however, these agents inhibit a wide variety of kinase targets and are associated with a range of adverse effects. More recently, a new generation TKI, axitinib, has been approved by the US Food and Drug Administration. Tivozanib is a novel TKI, which is a potent inhibitor of VEGF-1, VEGF-2, VEGF-3, c-kit, and PDGR kinases, with a more restricted target spectrum. Phase II and III studies have demonstrated significant activity and a favorable safety profile as an initial targeted treatment for advanced RCC. This review examines the emerging data with tivozanib for the treatment of advanced RCC. Preclinical investigations as well as Phase I, II, and III data are examined; data on the comparative benefits of tivozanib are reviewed. Finally, we discuss the future potential of tivozanib in combination, biomarkers associated with tivozanib response, and acquisition of resistance and nonkidney cancer indications. HubMed – drug


Participants’ Perceptions of a Multidisciplinary Training Program for Graduate and Postgraduate Students in Drug Use Management and Policy.

Am J Pharm Educ. 2013 Jun 12; 77(5): 102
Conrad P, Sketris I, Langille-Ingram E

Objective. To determine graduate and postgraduate students’ perceptions of a drug use management and policy program that applied wide-ranging policy research skills to inform pharmaceutical decision-making. Design. Nine cohorts of graduate and postgraduate students from diverse academic and professional backgrounds were paired with health-system preceptors for 4 months, and supported by faculty advisors and administrators, to complete research projects that generated evidence to inform policy decisions. Assessment. A self-administered survey instrument was sent to all alumni of the program over the previous 10 years. The majority of respondents indicated: their prior academic coursework could be applied to everyday life; service-learning projects complemented university programs; participation led to greater awareness of decision-makers’ needs and appreciation of their tacit knowledge; and communication abilities were enhanced with decision-makers, and academics. Many also reported personal desire to fulfill healthcare-system research needs; personal belief in their ability to make a difference; and increased postgraduation marketability. Conclusion. A drug use management and policy program allowed graduate students from various disciplines to develop new skills and collaborate with experts to produce research evidence that was relevant to drug policy that addressed real-world problems. HubMed – drug


The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials.

Ann Oncol. 2013 Jun 20;
Lyman GH, Dale DC, Culakova E, Poniewierski MS, Wolff DA, Kuderer NM, Huang M, Crawford J

The granulocyte colony-stimulating factor (G-CSF) is utilized to reduce neutropenic complications in patients receiving cancer chemotherapy. This study represents a systematic review and evidence summary of the impact of G-CSF support on chemotherapy dose intensity and overall mortality.All randomized controlled trials (RCTs) comparing chemotherapy with or without G-CSF support and reporting all-cause mortality with at least 2 years of follow-up were sought. Dual-blind data abstraction of disease, treatment, patient and outcome study results with conflict resolution by third party was carried out.The search revealed 61 randomized comparisons of chemotherapy with or without initial G-CSF support. Death was reported in 4251 patients randomized to G-CSFs and in 5188 controls. Relative risk (RR) with G-CSF support for all-cause mortality was 0.93 (95% confidence interval: 0.90-0.96; P < 0.001). RR for mortality varied by intended chemotherapy dose and schedule: same dose and schedule (RR = 0.96; P = 0.060), dose dense (RR = 0.89; P < 0.001), dose escalation (RR = 0.92; P = 0.019) and drug substitution or addition (RR = 0.94; P = 0.003). Greater RR reduction was observed among studies with longer follow-up (P = 0.02), where treatment was for curative intent (RR = 0.91; P < 0.001), and where survival was the primary outcome (RR = 0.91; P < 0.001).All-cause mortality is reduced in patients receiving chemotherapy with primary G-CSF support. The greatest impact was observed in RCTs in patients receiving dose-dense schedules. HubMed – drug