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Byline: Inderjeet. Singh, Vinu. Jose, Ronak. Patel, Sumit. Arora OBJECTIVE: The study assessed the efficacy, safety, pharmacokinetic (PK), and immunogenicity profiles of denosumab-biosimilar and denosumab-reference in postmenopausal osteoporotic women from [...]

Byline: Vinu. Jose, Swetha. Radhakrishna, Parag. Pipalava, Inderjeet. Singh Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in [...]

Drug-device combination products should be safe and effective for intended uses by intended users under intended use environment during human factor (HF) studies. All known use errors and use-related problems should be considered during design of device and use-related risk analysis. Availability of such information in a compiled manner is scarce. This review compiles information of use errors reported during HF validation studies of biological combination products (drug + device) approved by USFDA's Centre for Drug Evaluation and Research between 21 June 2011 and 31 December 2019. Information regarding product, indication, type of devices, use errors, root causes and mitigation strategies were collected from published documents. Total 280 use errors were reported during HF validation studies of 39 devices across 5 categories. Overall approach and methodology for use error data collection during HF validation studies was in line with the US FDA recommendations. Performance of participants for critical and essential tasks was evaluated during HF validation studies via simulated use assessment, knowledge task assessment and interview. The root causes for use errors reported during HF validation studies were identified and use errors were mitigated by suitable corrective measures. Instructions for use clarification/improvement and labelling improvement were the most common mitigation strategies implemented across devices. [ABSTRACT FROM AUTHOR]

Regulatory agencies of the USA and European Union (EU) have introduced multiple guidelines in the last decade to standardize and accelerate biosimilar development. As a result, a large number of biosimilars are being approved in the USA and EU. In the present review, we identified the biosimilars and their corresponding reference biologics approved for pediatrics in the USA and EU, and then assessed their approval details. In the USA, a biosimilar applicant needs to submit an initial pediatric study plan under the Pediatric Research Equity Act (PREA). We found that the PREA requirements of a pediatric assessment for biosimilars were waived where the reference biologics were not approved for one or more pediatric age groups for an indication. The PREA requirements of a pediatric assessment were deferred if the indication was under orphan drug exclusivity or a pediatric formulation was not available. Excluding the waiver and deferral scenarios, biosimilars were approved for the same pediatric indications as those of the reference biologics based on scientific justification extrapolation from the pediatric information of the reference biologics to biosimilars. The applicants were asked to submit a pediatric assessment in the deferred indication and/or develop a dedicated formulation that can ensure accurate dose delivery in pediatric population, as applicable. In the EU, pediatric assessments were not required for biosimilars; hence, all biosimilars (except rituximab) have been approved for the same indications as those of the reference biologics. Biosimilar developers need to be aware of the possible requirement of a pediatric study plan, development of pediatric drug delivery devices, and requirement of human factor studies for a device, to avoid delay in approval of biosimilars in the USA. [ABSTRACT FROM AUTHOR]

Byline: Vishal. Bansal, Bikash. Medhi, Vinu. Jose, P. Pandhi Sir, Advancement in antimicrobials (AMs) has resulted in good success rates for life-threatening infections. However, the selection of AM is largely [...]

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between‐meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo‐controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose‐lowering effect (glucose area under concentration‐time curve [AUC]) compared to the 30‐minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between‐meal interval. The 6‐hour between‐meal interval resulted in better absorption of insulin tregopil in comparison to 4‐ and 5‐hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0‐180min in the insulin tregopil 4‐hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high‐fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high‐fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5‐hour between‐meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Oral insulin tregopil (IN‐105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN‐105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN‐105 on pharmacokinetics (PKs) of metformin. In this randomized, open‐label, cross‐over study, metformin was administered to healthy volunteers receiving IN‐105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC0‐inf; fasting and fed) and peak plasma concentration (Cmax; fed) of metformin were within 0.80–1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN‐105 on PKs of metformin under fasting/fed conditions, and it was safe. [ABSTRACT FROM AUTHOR]

The reliability of differential gene expression analysis on formalin-fixed, paraffin-embedded (FFPE) expression profiles generated using Affymetrix arrays is questionable, due to the high range of percent-present values reported in studies which profiled FFPE samples using this technology. Moreover, the validity of gene-modules derived from external datasets in FFPE microarray expression profiles is unknown. By generating matched gene expression profiles using RNAs derived from fresh-frozen (FF) and FFPE preserved breast tumors with Affymetrix arrays and FF/FFPE RNA specific amplification-and-labeling kits, the reliability of differential expression analysis and the validity of gene modules derived from external datasets were investigated. Specifically, the reliability of differential expression analysis was investigated by developing de-novo ER/HER2 pathway gene-modules from the matched datasets and validating them on external FF/FFPE gene expression datasets using ROC analysis. Spearman's rank correlation coefficient of module scores between matched FFPE/frozen datasets was used to measure the reliability of gene-modules derived from external datasets in FFPE expression profiles. Independent of the array/amplification-kit/sample preservation method used, de-novo ER/HER2 gene-modules derived from all matched datasets showed similar prediction performance in the independent validation (AUC range in FFPE dataset; ER: 0.93–0.95, HER2: 0.85–0.91), except for the de-novo ER/HER2 gene-module derived from the FFPE dataset using the 3'IVT kit (AUC range in FFPE dataset; ER: 0.79–0.81, HER2: 0.78). Among the external gene modules considered, roughly ~50% gene modules showed high concordance between expression profiles derived from matching FF and FFPE RNA. The remaining discordant gene modules between FF and FFPE expression profiles showed high concordance within matching FF datasets and within matching FFPE datasets independently, implying that microarrays still require improved amplification-and-sample-preparation protocols for deriving 100% concordant expression profiles from matching FF and FFPE RNA. [ABSTRACT FROM AUTHOR]

Breast cancer during pregnancy is rare and is associated with relatively poor prognosis. No information is available on its biological features at the genomic level. Using a dataset of 54 pregnant and 113 non-pregnant breast cancer patients, we evaluated the pattern of hot spot somatic mutations and did transcriptomic profiling using Sequenom and Affymetrix respectively. We performed gene set enrichment analysis to evaluate the pathways associated with diagnosis during pregnancy. We also evaluated the expression of selected cancer-related genes in pregnant and non-pregnant patients and correlated the results with changes occurring in the normal breast using a pregnant murine model. We finally investigated aberrations associated with disease-free survival (DFS). No significant differences in mutations were observed. Of the total number of patients, 18.6% of pregnant and 23% of non-pregnant patients had a PIK3CA mutation. Around 30% of tumors were basal, with no differences in the distribution of breast cancer molecular subtypes between pregnant and non-pregnant patients. Two pathways were enriched in tumors diagnosed during pregnancy: the G protein-coupled receptor pathway and the serotonin receptor pathway (FDR !0.0001). Tumors diagnosed during pregnancy had higher expression of PD1 (PDCD1; PZ0.015), PDL1 (CD274; PZ0.014), and gene sets related to SRC (PZ0.004), IGF1 (PZ0.032), and b-catenin (PZ0.019). Their expression increased almost linearly throughout gestation when evaluated on the normal breast using a pregnant mouse model underscoring the potential effect of the breast microenvironment on tumor phenotype. No genes were associated with DFS in a multivariate model, which could be due to low statistical power. Diagnosis during pregnancy impacts the breast cancer transcriptome including potential cancer targets. [ABSTRACT FROM AUTHOR]