Development of a pediatric relative bioavailability/bioequivalence database and identification of putative risk factors associated with evaluation of pediatric oral products

Generally, bioequivalence (BE) studies of drug products for pediatric patients are conducted in adults due to ethical reasons. Given the lack of direct BE assessment in pediatric populations, the aim of this work is to develop a database of BE and relative bioavailability (relative BA) studies conducted in pediatric populations and to enable the identification of risk factors associated with certain drug substances or products that may lead to failed BE or different pharmacokinetic (PK) parameters in relative BA studies in pediatrics. A literature search from 1965 to 2020 was conducted in PubMed, Cochrane Library, and Google Scholar to identify BE studies conducted in pediatric populations and relative BA studies conducted in pediatric populations. Overall, 79 studies covering 37 active pharmaceutical ingredients (APIs) were included in the database: 4 bioequivalence studies with data that passed BE evaluations; 2 studies showed bioinequivalence results; 34 relative BA studies showing comparable PK parameters, and 39 relative BA studies showing differences in PK parameters between test and reference products. Based on the above studies, common putative risk factors associated with differences in relative bioavailability (DRBA) in pediatric populations include age-related absorption effects, high inter-individual variability, and poor study design. A database containing 79 clinical studies on BE or relative BA in pediatrics has been developed. Putative risk factors associated with DRBA in pediatric populations are summarized

Integration of biorelevant pediatric dissolution methodology into PBPK modeling to predict in vivo performance and bioequivalence of generic drugs in pediatric populations : a carbamazepine case study

This study investigated the impact of gastro-intestinal fluid volume and bile salt (BS) concentration on the dissolution of carbamazepine (CBZ) immediate release (IR) 100 mg tablets and to integrate these in vitro biorelevant dissolution profiles into physiologically based pharmacokinetic modelling (PBPK) in pediatric and adult populations to determine the biopredictive dissolution profile. Dissolution profiles of CBZ IR tablets (100 mg) were generated in 50–900 mL biorelevant adult fasted state simulated gastric and intestinal fluid (Ad-FaSSGF and Ad-FaSSIF), also in three alternative compositions of biorelevant pediatric FaSSGF and FaSSIF medias at 200 mL. This study found that CBZ dissolution was poorly sensitive to changes in the composition of the biorelevant media, where dissimilar dissolution (F2 = 46.2) was only observed when the BS concentration was changed from 3000 to 89 μM (Ad-FaSSIF vs Ped-FaSSIF 50% 14 BS). PBPK modeling demonstrated the most predictive dissolution volume and media composition to forecast the PK was 500 mL of Ad-FaSSGF/Ad-FaSSIF media for adults and 200 mL Ped-FaSSGF/FaSSIF media for pediatrics. A virtual bioequivalence simulation was conducted by using Ad-FaSSGF and/or Ad-FaSSIF 500 mL or Ped-FaSSGF and/or Ped-FaSSIF 200 mL dissolution data for CBZ 100 mg (reference and generic test) IR product. The CBZ PBPK models showed bioequivalence of the product. This study demonstrates that the integration of biorelevant dissolution data can predict the PK profile of a poorly soluble drug in both populations. Further work using more pediatric drug products is needed to verify biorelevant dissolution data to predict the in vivo performance in pediatrics. Graphical Abstract

The lncRNA MALAT1 rs619586 G Variant Confers Decreased Susceptibility to Recurrent Miscarriage

Cardiovascula disease and recurrent miscarriage have shared risk factors, and some cardiovascular disease-related candidate genes have been confirmed to be associated with recurrent miscarriage. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that is considered to be associated with susceptibility to cardiovascular disease. However, whether lncRNA MALAT1 polymorphisms are related to recurrent miscarriage susceptibility is unclear. We genotyped three lncRNA MALAT1 polymorphisms (rs591291, rs619586, and rs3200401) in 284 patients and 392 controls using TaqMan methods. Logistic regression was used to evaluate the odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age. Our results showed that the rs619586 G variant had protective effects against recurrent miscarriage (AG vs. AA: adjusted OR = 0.670, 95% CI = 0.457–0.982, p = 0.040; GG vs. AA: adjusted OR = 0.278, 95% CI = 0.079–0.975, p = 0.046; GG/AG vs. AA adjusted OR = 0.621, 95% CI = 0.429–0.900, p = 0.012). In a combined analyses of protective genotypes, with regard to the three single nucleotide polymorphisms (SNPs), we found that individuals with two or three protective genotypes exhibited a significantly lower risk of recurrent miscarriage than those with no or only one protective genotype (adjusted OR = 0.369, 95% CI = 0.199–0.684, p = 0.002). Moreover, the decrease in recurrent miscarriage risk with two or three protective genotypes was most pronounced in women less than 35 years of age (OR = 0.290, 95% CI = 0.142–0.589, p < 0.001) and in women with 2–3 miscarriages (adjusted OR = 0.270, 95% CI = 0.126–0.580, p < 0.001). In conclusion, our study suggests that the rs619586 G variant may have potential protective effects conferring a decreased risk of recurrent miscarriage in the southern Chinese population

Syntheses And Biological Activities Of Disaccharide Daunorubicins

Carbohydrate moiety is found in many anticancer nature products. To explore the carbohydrate moiety of daunorubicin in enhancing anticancer efficacy, several daunorubicin derivatives bearing disaccharide (1-8) have been synthesized. Their cytotoxicities were tested in leukemia K562 and colon cancer SW620 cells. Topoisomerase II (topo II) poisoning was performed with the in vivo complex of topoisomerase bioassay. In both cell lines, compounds with various terminal 2,6-dideoxy sugars (compounds 1, 3, 5, and 8) showed 30- to 60-fold higher anticancer activity than compounds with 2-deoxy- or 6-deoxy sugar (compounds 6 and 7). Compounds with an α-linkage between two sugar units (compound 3) showed 35-fold higher anticancer activity than compounds with a β-linkage (compound 4). In addition, the anticancer activities of these compounds correlated with their ability to target topo II mediated genomic DNA damage in vivo. Compounds 1 and 3 with 2,6-dideoxy sugars produced more covalent topo-DNA complex than compounds with 2-deoxy sugar (6) and 6-deoxy sugar (7). Compounds with an α-configuration of terminal 2,6-dideoxy sugar (compounds 1 and 3) showed higher topo II poisoning than their counterparts with the β-configuration (compounds 2 and 4). These results indicate that sugar moieties in daunorubicin play a significant role in its anticancer activity and topo II inhibition. The second sugar of disaccharide daunorubicin should possess 2,6-dideoxy with α-linkage to the first sugar to exhibit better anticancer activity. © 2005 American Chemical Society

ABCC4 Variants Modify Susceptibility to Kawasaki Disease in a Southern Chinese Population

A previous family-based linkage study revealed that Kawasaki disease (KD) was associated with variations of the ATP-binding cassette subfamily C member 4 (ABCC4) gene in most European populations. However, significant differences exist among ethnic populations in European and Chinese subjects; therefore, whether ABCC4 variants indicate susceptibility to KD in Chinese children is unclear. The purpose of this research was to evaluate correlations between ABCC4 gene polymorphisms and susceptibility to KD in a Southern Chinese population. We genotyped six polymorphisms (rs7986087, rs868853, rs3765534, rs1751034, rs3742106, and rs9561778) in 775 KD patients and 774 healthy controls. Ninety-five percent confidence intervals (95% CIs) and odds ratios (ORs) were used to assess the strength of each association. We found that the rs7986087 T variant genotype was associated with significantly higher susceptibility to KD (adjusted OR = 1.30, 95% CI = 1.05–1.60 for rs7986087 CT/TT). However, the rs868853 T variant genotype was associated with significantly lower susceptibility to KD (adjusted OR = 0.74, 95% CI = 0.59–0.92 for rs868853 CT/CC). Compared with the patients with 0–4 ABCC4 risk genotypes, the patients with 5-6 ABCC4 risk genotypes had a significantly increased risk of KD (adjusted OR = 1.63, 95% CI = 1.07–2.47), and this risk was more significant in the subgroups of females, subjects aged 12–60 months, and individuals with coronary artery lesions. These results indicate that specific single-nucleotide polymorphisms in the ABCC4 gene may increase susceptibility to KD in a Southern Chinese population