Pharmacokinetics and bioequivalence of generic and branded abiraterone acetate tablet: a single-dose, open-label, and replicate designed study in healthy Chinese male volunteers

Abstract

Purpose

Abiraterone acetate is a highly variable drug and has been approved for the treatment of patients with metastatic castration-resistant prostate cancer in many countries. This study was conducted to compare the pharmacokinetic profile between the test product (abiraterone acetate tablet) and reference product ZYTIGA® (250 mg) mainly.

Methods

To overcome the high intra-subject variability of abiraterone, a two-sequence and four-period crossover study was designed to assess bioequivalence between the two products in 32 healthy male Chinese subjects under fasting conditions. The plasma concentration of abiraterone was analyzed by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters.

Results

The point estimate of geometric mean ratios with 90% confidence interval (CI) of maximum observed concentration (C_max) and the area under the concentration–time curve (AUC_0t) for abiraterone in the test and reference products were 100.19% (90% CI 87.05–115.32%) and 105.99% (90% CI 96.34–116.62%), respectively, and were both within the range of 80.00–125.00%. The 95% confidence upper limit bound for \({({\bar {Y}_{\text{T}}} - {\overline {Y} _{\text{R}}})^{\text{2}}}~ - ~\theta S_}}^}{\text{ }}\) was − 0.1079 for C_max and was − 0.0515 for AUC_0t.

Conclusions

Bioequivalence was demonstrated between the two abiraterone acetate products. The study also confirmed high intra-subject variability, for abiraterone: coefficient of variation (CV, %) of C_max values for the test and reference products were 40.33% and 46.58%, while for AUC_0t were 24.02% and 34.16%, respectively.

Trial registration

http://www.chinadrugtrials.org.cn/: CTR20170997.

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The Qualified Presumption of Safety assessment and its role in EFSA risk evaluations: fifteen years past

Abstract

Microorganisms (food or feed additive, novel food or plant protection product) are intentionally added at different stages of the food and feed chain and are subjected to regulation and safety assessment by the European Food Safety Authority (EFSA). Safety evaluation is based on application dossiers for market authorisation to the European Commission. The qualified presumption of safety (QPS) concept was developed in 2003 to provide a harmonised generic safety pre-appraisal of the above microorganisms. Unambiguously defined biological taxonomic units (TUs) are assessed for their body of knowledge, their safety and their end use. Identified safety concerns for a certain TU can be, where reasonable in number and not universally present, reflected as 'qualifications'. Strains belonging to TUs having QPS status may benefit of a fast track evaluation. The lowest TU for which the QPS status is granted is the species level for bacteria and yeasts and the family for viruses. The QPS concept is also applicable to genetically modified microorganisms used for production purposes,. Based on the current body of knowledge and/or the ambiguous taxonomic position, some TUs, such as filamentous fungi, bacteriophages, Enterococcus faecium, Escherichia coli, Streptomyces spp. and Oomycetes are not considered liable for QPS status.

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Cancers, Vol. 10, Pages 504: Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases

Cancers, Vol. 10, Pages 504: Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases

Cancers doi: 10.3390/cancers10120504

Authors: Pauline Roussille Gaelle Tachon Claire Villalva Serge Milin Eric Frouin Julie Godet Antoine Berger Sheik Emambux Christos Petropoulos Michel Wager Lucie Karayan-Tapon David Tougeron

Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.

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PIE-1 Translation in the Germline Lineage Contributes to PIE-1 Asymmetry in the Early Caenorhabditis elegans Embryo

In the C. elegans embryo, the germline lineage is established through successive asymmetric cell divisions that each generate a somatic and a germline daughter cell. PIE-1 is an essential maternal factor that is enriched in embryonic germline cells and is required for germline specification. We estimated the absolute concentration of PIE-1::GFP in germline cells and find that PIE-1::GFP concentration increases by roughly 4.5 fold, from 92 nM to 424 nM, between the 1 and 4-cell stages. Previous studies have shown that the preferential inheritance of PIE-1 by germline daughter cells and the degradation of PIE-1 in somatic cells are important for PIE-1 enrichment in germline cells. In this study, we provide evidence that the preferential translation of maternal PIE-1::GFP transcripts in the germline also contributes to PIE-1::GFP enrichment. Through an RNAi screen, we identified Y14 and MAG-1 (Drosophila tsunagi and mago nashi) as regulators of embryonic PIE-1::GFP levels. We show that Y14 and MAG-1 do not regulate PIE-1 degradation, segregation or synthesis in the early embryo, but do regulate the concentration of maternally-deposited PIE-1::GFP. Taken together, or findings point to an important role for translational control in the regulation of PIE-1 levels in the germline lineage.

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Integrative Analysis of Transcriptomic and Methylomic Data in Photoperiod-Dependent Regulation of Cucumber Sex Expression

The cucumber (Cucumis sativus) is characterized by its diversity and seasonal plasticity in sexual type. A long day length condition significantly decreased the cucumber female flower ratio by 17.7–52.9%, and the effect of photoperiod treatment is more significant under low temperature than under high temperature. Transcriptome analysis indicates that the photoperiod treatment preferentially significantly influenced flower development processes, particularly MADS-box genes in shoot apices. The long-day treatment resulted in predominantly transposable element (TE)- and gene-associated CHH-types of DNA methylation changes. Nevertheless, there was significant enrichment of CG- and CHG-types of DNA methylation changes nearing transcription start sites (TSSs)/transcription end sites (TESs) and gene bodies, respectively. Predominantly negative association between differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were observed which implied epiregulation of DEGs. Two MADS-box genes that were significantly downregulated by long photoperiod showed significant hypermethylation in promoter regions that is essentially TE-rich. This study indicates MADS-box genes which are partially regulated by promoter methylation state may mediate photoperiod-dependent regulation of cucumber sex expression.

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Phenomic Selection Is a Low-Cost and High-Throughput Method Based on Indirect Predictions: Proof of Concept on Wheat and Poplar

Genomic selection - the prediction of breeding values using DNA polymorphisms - is a disruptive method that has widely been adopted by animal and plant breeders to increase productivity. It was recently shown that other sources of molecular variations such as those resulting from transcripts or metabolites could be used to accurately predict complex traits. These endophenotypes have the advantage of capturing the expressed genotypes and consequently the complex regulatory networks that occur in the different layers between the genome and the phenotype. However, obtaining such omics data at very large scales, such as those typically experienced in breeding, remains challenging. As an alternative, we proposed using near-infrared spectroscopy (NIRS) as a high-throughput, low cost and non-destructive tool to indirectly capture endophenotypic variants and compute relationship matrices for predicting complex traits, and coined this new approach "phenomic selection" (PS). We tested PS on two species of economic interest (Triticum aestivum L. and Populus nigra L.) using NIRS on various tissues (grains, leaves, wood). We showed that one could reach predictions as accurate as with molecular markers, for developmental, tolerance and productivity traits, even in environments radically different from the one in which NIRS were collected. Our work constitutes a proof of concept and provides new perspectives for the breeding community, as PS is theoretically applicable to any organism at low cost and does not require any molecular information.

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Genetic Contributions to Ectopic Sperm Cell Migration in Caenorhabditis Nematodes

Reproductive barriers involving gametic incompatibilities can act to enhance population divergence and promote the persistence of species boundaries. Observing gametic interactions in internal fertilizing organisms, however, presents a considerable practical challenge to characterizing mechanisms of such gametic isolation. Here we exploit the transparency of Caenorhabditis nematodes to investigate gametic isolation mediated by sperm that can migrate to ectopic locations, with this sperm invasion capable of inducing female sterility and premature death. As a step toward identifying genetic factors and mechanisms associated with female susceptibility to sperm invasion, we characterized a panel of 25 C. elegans genetic mutants to test for effects on the incidence and severity of sperm invasion in both conspecific and inter-species matings. We found genetic perturbations to contribute to distinct patterns of susceptibility that identify ovulation dynamics and sperm guidance cues as modulators of ectopic sperm migration incidence and severity. Genotypes confer distinctive phenotypic sensitivities to the sperm from conspecific C. elegans males vs. heterospecific C. nigoni males, implicating evolution of functional divergence in the history of these species for components of sperm-reproductive tract interactions. Sexually-antagonistic co-evolution within species that drives divergent trait and molecular evolution between species provides a working model to explain mismatched species-specific gametic interactions that promote or mitigate ectopic sperm migration.

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