Halichondrin B is a complex, natural, polyether macrolide derived from marine sponges. Eribulin is a structurally-simplified, synthetic, macrocyclic ketone analogue of Halichondrin B. Eribulin was approved by United States Food and Drug Administration in 2010 as a third-line therapy for metastatic breast cancer patients who have previously been treated with an anthracycline and a taxane. It has a unique microtubule dynamics inhibitory action. Phase III studies have either been completed or are currently ongoing in breast cancer, soft tissue sarcoma, and non-small cell lung cancer. Phase I and II studies in multiple cancers and various combinations are currently ongoing. This article reviews the available information on eribulin with respect to its clinical pharmacology, pharmacokinetics, pharmacodynamics, mechanism of action, metabolism, preclinical studies, and with special focus on clinical trials.

Sodium starch glycolate is a commonly used super-disintegrant employed to promote rapid disintegration and dissolution of IR solid dosage forms. It is manufactured by chemical modification of starch, i.e., carboxymethylation to enhance hydrophilicity and cross-linking to reduce solubility. It has been reported in the literature that the source of starch, particle size, amount of sodium chloride (reaction by-product), viscosity, degree of substitution and cross-linking affect the functionality of sodium starch glycolate. Compendial assays provide an accurate representation of the chemical quality of an excipient, but they are not useful in describing the physical properties associated with the excipients. Physical characterization of sodium starch glycolate, NF revealed differences in particle size, surface area, porosity, surface morphology, and viscosity between two of the three sources examined. An automated liquid uptake test (in neutral and acidic medium) demonstrated similar initial rates of uptake, however, the extent of liquid uptake differed for the disintegrant powders examined. Settling volume was also observed to be different for the disintegrant from two sources. Lowering the pH of the medium reduced the rate and extent of liquid uptake and the settling volume in all instances. The extent of liquid uptake and settling volume was observed to be higher for the smaller sieve fractions in either medium, Although differences were also observed in the axial and radial disintegration force measurements of the pure disintegrant compacts, disintegration and dissolution of a model drug (hydrochlorothiazide) from either the soluble or insoluble core did not reveal any significant differences between the multiple sources.

In the past two decades, three categories of newer disintegrants have come into widespread use. These substances are a synthetic polymer (crospovidone), chemically modified starch (sodium starch glycolate) and cellulose (croscarmellose sodium). Multiple suppliers are now available for each category. Current NF monographs do not provide tests which reflect on their functionality and one cannot assume reliable performance of disintegrants from different sources meeting NF standards. The objective of this study was to identify differences in physical properties thought to be related to functionality among crospovidones from multiple sources. Physical properties examined included particle size and distribution, surface area, porosity and surface morphology. Disintegration and dissolution were performed on a model tablet formulation using either an insoluble or a soluble filler. Substantial differences in particle size and distribution, surface area, porosity and surface morphology were observed which correlated with differences in disintegration time and dissolution rate of the model drug from an insoluble tablet core. None of the differences in physical properties resulted in any differences in the disintegration or dissolution of the model drug from a soluble tablet core.

◥KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a doublestranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m 2 ) and pelareorep (1 Â 10 10 TCID 50 -3 Â 10 10 TCID 50 )] was implemented in adult patients with oxaliplatin refractory/intolerant, KRASmutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-na€ ve patients, the highest dose of FOLFIRI/ bevacizumab (180 mg/m 2 irinotecan) and pelareorep (3 Â 10 10 TCID 50 ) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid s-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/ bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.