Subcutaneous versus Intravenous Bortezomib Administration for Multiple Myeloma Patients：a Meta-analysis

Bortezomib,the first potent therapeutic proteasome inhibitor,has been suggested as a standard care in patients with newly diagnosed and relapsed multiple myeloma（MM）.However,evidence bearing on the efficacy and safety of subcutaneous（SC） versus intravenous（IV） administration of bortezomib for MM patients is controversial.Randomised controlled trials（RCTs） and observational studies were enrolled in our meta-analysis to investigate the efficacy and safety of bortezomib via SC vs.IV administration on MM patients.Sixteen trials with a total of 2575 patients with MM（SC,n=1191;IV,n=1384） were included in our meta-analysis.There were no significant differences between these two arms regarding overall response rate（ORR）,complete response（CR）,or very good partial response（VGPR）.The pooled RRs for rate of adverse events（AEs）,such as thrombocytopenia and bortezomib-induced peripheral neuropathy（BIPN）,were 0.79（95% CI：0.68–0.92） and 0.63（95% CI：0.51–0.79）,respectively.Moreover,there was much more largely decreased incidence of grade 3 and higher thrombocytopenia and BIPN in bortezomib SC administration than IV route.In general,alternative SC administration should be considered instead of IV administration in use of bortezomib for patients with MM.

Supramolecular approaches for insulin stabilization without prolonged duration of action

Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics.The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol(CB[7]-PEG)has been shown to stabilize insulin formulations by reducing aggregation propensity.Yet prolonged in vivo duration of action,arising from sustained complex formation in the subcutaneous depot,limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal.Supramolecular affinity of CB[7]in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach.Accordingly,here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7]interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation.These insulin analogs show weak to no interaction with CB[7]-PEG at physiological pH but demonstrate high formulation stability at reduced pH.Accordingly,N-terminal modified analogs have in vitro and in vivo bioactivity comparable to native insulin.Furthermore,in a rat model of diabetes,the acid-modified insulin formulated with CB[7]-PEG offers a reduced duration of action compared to native insulin formulated with CB[7]-PEG.This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging in vivo duration of action.

Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics

Diabetes mellitus is a major health problem with increasing prevalence at a global level.The discovery of insulin in the early 1900 s represented a major breakthrough in diabetes management,with further milestones being subsequently achieved with the identification of glucagon-like peptide-1(GLP-1)and the introduction of GLP-1 receptor agonists(GLP-1 RAs)in clinical practice.Moreover,the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption.However,current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation.In this review,we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.