FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

Bioequivalence Study Methods with Pharmacokinetic Endpoints for Topical Ophthalmic Corticosteroid Suspensions and Effects of Subject Demographics.

PURPOSE: To establish bioequivalence for topical ophthalmic corticosteroid suspensions, some of U.S. product-specific guidances (PSGs) for generic drug products recommend evaluation of aqueous humor (AH) pharmacokinetics (PK). However, the AH PK study is complex because the relationships among AH PK, subject demographics, ocular anatomy, physiology and the compounds' physicochemical characteristics are not well understood. The objective of this research is to provide an overview of the in vivo human AH studies submitted to the U.S. Food and Drug Administration (FDA) for ophthalmic corticosteroid suspensions and to investigate the impact of subject demographics on the human AH PK. METHODS: We summarized demographic data, sampling time points, sample size per time point and PK parameters to investigate correlations in the studies submitted to the FDA. RESULTS: In the evaluation of subject-specific covariates, the area under the concentration-time curves (AUC) and maximum concentrations (Cmax) were significantly different among ethnicities and age groups. Gender was not primarily associated with differences in AH PK. CONCLUSIONS: Our results suggest that the difference in ethnicity and age of the study population play an important role in the AH PK profiles of topical ophthalmic corticosteroid suspensions. Considering the subject-specific covariate effects in designing bioequivalence studies with AH PK endpoints could reduce bias from covariate imbalance and help identify true effects of formulation differences.

N-methylnicotinamide and nicotinamide N-methyltransferase are associated with microRNA-1291-altered pancreatic carcinoma cell metabolome and suppressed tumorigenesis.

The cell metabolome comprises abundant information that may be predictive of cell functions in response to epigenetic or genetic changes at different stages of cell proliferation and metastasis. An unbiased ultra-performance liquid chromatography-mass spectrometry-based metabolomics study revealed a significantly altered metabolome for human pancreatic carcinoma PANC-1 cells with gain-of-function non-coding microRNA-1291 (miR-1291), which led to a lower migration and invasion capacity as well as suppressed tumorigenesis in a xenograft tumor mouse model. A number of metabolites, including N-methylnicotinamide, involved in nicotinamide metabolism, and l-carnitine, isobutyryl-carnitine and isovaleryl-carnitine, involved in fatty acid metabolism, were elevated in miR-1291-expressing PANC-1. Notably, N-methylnicotinamide was elevated to the greatest extent, and this was associated with a sharp increase in nicotinamide N-methyltransferase (NNMT) mRNA level in miR-1291-expressing PANC-1 cells. In addition, expression of NNMT mRNA was inversely correlated with pancreatic tumor size in the xenograft mouse model. These results indicate that miR-1291-altered PANC-1 cell function is associated with the increase in N-methylnicotinamide level and NNMT expression, and in turn NNMT may be indicative of the extent of pancreatic carcinogenesis.

Abnormal expression of an ADAR2 alternative splicing variant in gliomas downregulates adenosine-to-inosine RNA editing.

BACKGROUND: RNA editing is catalyzed by adenosine deaminases acting on RNA (ADARs). ADAR2 is the main enzyme responsible for recoding editing in humans. Adenosine-to-inosine (A-to-I) editing at the Q/R site is reported to be decreased in gliomas; however, the expression of ADAR2 mRNA was not greatly affected. METHODS: We determined ADAR2 mRNA expression in human glioblastoma cell lines and in normal human glial cells by real-time RT-PCR. We also determined ADAR2 mRNA expression in 44 glioma tissues and normal white matter. After identifying an alternative splicing variant (ASV) of ADAR2 in gliomas, we performed sequencing. We then classified glioblastomas based on the presence (+) or absence (-) of the ASV to determine the correlations between ASV + and malignant features of glioblastomas, such as invasion, peritumoral brain edema, and survival time. RESULTS: There were no significant differences in ADAR2 mRNA expression among human glioblastoma cell lines or in gliomas compared with normal white matter (all p > 0.05). The ASV, which contained a 47-nucleotide insertion in the ADAR2 mRNA transcript, was detected in the U251 and BT325 cell lines, and in some glioma tissues. The expression rate of ASV differed among gliomas of different grades. ASV + glioblastomas were more malignant than ASV - glioblastomas. CONCLUSIONS: ADAR2 is a family of enzymes in which ASVs result in differences in enzymatic activity. The ADAR2 ASV may be correlated with the invasiveness of gliomas. Identification of the mechanistic characterization of ADAR2 ASV may have future potential for individualized molecular targeted-therapy for glioma.

Small nucleolar RNA-derived microRNA hsa-miR-1291 modulates cellular drug disposition through direct targeting of ABC transporter ABCC1.

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is an important membrane transporter that contributes to cellular disposition of many endobiotic and xenobiotic agents, and it can also confer multidrug resistance. This study aimed to investigate the role of human noncoding microRNA-1291 (hsa-miR-1291) in regulation of ABCC1 and drug disposition. Bioinformatics analyses indicated that hsa-miR-1291, localized within the small nucleolar RNA H/ACA box 34 (SNORA34), might target ABCC1 3'-untranslated region (3'UTR). Using splinted ligation small RNA detection method, we found that SNORA34 was processed into hsa-miR-1291 in human pancreatic carcinoma PANC-1 cells. Luciferase reporter assays showed that ABCC1 3'-UTR-luciferase activity was decreased by 20% in cells transfected with hsa-miR-1291 expression plasmid, and increased by 40% in cells transfected with hsa-miR-1291 antagomir. Furthermore, immunoblot study revealed that ABCC1 protein expression was sharply reduced in hsa-miR-1291-stably transfected PANC-1 cells, which was attenuated by hsa-miR-1291 antagomir. The change of ABCC1 protein expression was associated with an alternation in mRNA expression. In addition, hsa-miR-1291-directed downregulation of ABCC1 led to a greater intracellular drug accumulation and sensitized the cells to doxorubicin. Together, our results indicate that hsa-miR-1291 is derived from SNORA34 and modulates cellular drug disposition and chemosensitivity through regulation of ABCC1 expression. These findings shall improve the understanding of microRNA-controlled epigenetic regulatory mechanisms underlying multidrug resistance and interindividual variability in pharmacokinetics.

miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3'UTRs of human genes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) can lead to the susceptibility and onset of diseases through their effects on gene expression at the posttranscriptional level. Recent findings indicate that SNPs could create, destroy, or modify the efficiency of miRNA binding to the 3'UTR of a gene, resulting in gene dysregulation. With the rapidly growing number of published disease-associated SNPs (dSNPs), there is a strong need for resources specifically recording dSNPs on the 3'UTRs and their nucleotide distance from miRNA target sites. We present here miRdSNP, a database incorporating three important areas of dSNPs, miRNA target sites, and diseases. DESCRIPTION: miRdSNP provides a unique database of dSNPs on the 3'UTRs of human genes manually curated from PubMed. The current release includes 786 dSNP-disease associations for 630 unique dSNPs and 204 disease types. miRdSNP annotates genes with experimentally confirmed targeting by miRNAs and indexes miRNA target sites predicted by TargetScan and PicTar as well as potential miRNA target sites newly generated by dSNPs. A robust web interface and search tools are provided for studying the proximity of miRNA binding sites to dSNPs in relation to human diseases. Searches can be dynamically filtered by gene name, miRBase ID, target prediction algorithm, disease, and any nucleotide distance between dSNPs and miRNA target sites. Results can be viewed at the sequence level showing the annotated locations for miRNA target sites and dSNPs on the entire 3'UTR sequences. The integration of dSNPs with the UCSC Genome browser is also supported. CONCLUSION: miRdSNP provides a comprehensive data source of dSNPs and robust tools for exploring their distance from miRNA target sites on the 3'UTRs of human genes. miRdSNP enables researchers to further explore the molecular mechanism of gene dysregulation for dSNPs at posttranscriptional level. miRdSNP is freely available on the web at http://mirdsnp.ccr.buffalo.edu.

Biochar and Cropping Systems Changed Soil Copper Speciation and Accumulation in Sweet Corn and Soybean.

In order to explore the effects of biochar and cropping systems on soil copper (Cu) speciation and copper accumulation in sweet corn (Zea mays L. var. Rugosa Bonaf.) and soybean (Glycine max (L.) Merr.), three ratios of biochar (C0, 0%, C1, 2%, C2, 5% by mass ratio, (w/w)) and three cropping systems (monocropped sweet corn, MC; monocropped soybean, MS; sweet corn-soybean intercropping, CS) were studied under three Cu levels (Cu0, 0 mg·kg-1, Cu1, 200 mg·kg-1, and Cu2, 400 mg·kg-1) in a pot experiment. The following results were obtained: (1) Compared with C0, adding biochar (C1, C2) could significantly reduce the Cu concentration in sweet corn, and C2 significantly reduced the Cu concentration in soybean under Cu1 and Cu2; the Cu concentrations in sweet corn and soybeans under Cu1 were lower than 10 mg·kg-1. (2) Compared with MC or MS, C2 significantly reduced the Cu concentration (below the detection limit) in sweet corn and the Cu concentration (1.65 mg·kg-1) in soybean straw in CS under Cu1. The Cu concentration in sweet corn ears and soybean straw in CS under Cu2 also decreased significantly, reaching 1.84 and 10.36 mg·kg-1, respectively. (3) Compared with C0, C2 significantly reduced the soil acid-soluble Cu concentration under Cu1 and Cu2, but significantly increased soil oxidated Cu concentration. (4) Compared with MC, the concentration of soil acid-soluble Cu was significantly decreased in CSC1 under Cu2. Under Cu1, the concentrations of reducible Cu were significantly increased in CSC1 and CSC2, and the oxidizable Cu concentration was increased in CSC2. In conclusion, sweet corn-soybean intercropping combined with biochar 5% (w/w) is beneficial to reducing the concentration of acid-soluble Cu, and increases the concentration of oxidizable Cu in copper-contaminated soil. Under Cu1 (200 mg·kg-1), the Cu concentrations in sweet corn and soybean were lower than 10 mg·kg-1, which meets the national food safety standard of China. Under Cu2 (400 mg·kg-1), the Cu concentration in sweet corn was lower than 10 mg·kg-1, but it was higher than 10 mg·kg-1 in soybean.

Quantitative methods and modeling to assess COVID-19-interrupted in vivo pharmacokinetic bioequivalence studies with two reference batches.

The coronavirus disease 2019 (COVID-19) has presented unprecedented challenges to the generic drug development, including interruptions in bioequivalence (BE) studies. Per guidance published by the US Food and Drug Administration (FDA) during the COVID-19 public health emergency, any protocol changes or alternative statistical analysis plan for COVID-19-interrupted BE study should be accompanied with adequate justifications and not lead to biased equivalence determination. In this study, we used a modeling and simulation approach to assess the potential impact of study outcomes when two different batches of a Reference Standard (RS) were to be used in an in vivo pharmacokinetic BE study due to the RS expiration during the COVID-19 pandemic. Simulations were performed with hypothetical drugs under two scenarios: (1) uninterrupted study using a single batch of an RS, and (2) interrupted study using two batches of an RS. The acceptability of BE outcomes was evaluated by comparing the results obtained from interrupted studies with those from uninterrupted studies. The simulation results demonstrated that using a conventional statistical approach to evaluate BE for COVID-19-interrupted studies may be acceptable based on the pooled data from two batches. An alternative statistical method which includes a "batch" effect to the mixed effects model may be used when a significant "batch" effect was found in interrupted four-way crossover studies. However, such alternative method is not applicable for interrupted two-way crossover studies. Overall, the simulated scenarios are only for demonstration purpose, the acceptability of BE outcomes for the COVID19-interrupted studies could be case-specific.

MicroRNA expression is differentially altered by xenobiotic drugs in different human cell lines.

Several noncoding microRNAs (miR or miRNA) have been shown to regulate the expression of drug-metabolizing enzymes and transporters. Xenobiotic drug-induced changes in enzyme and transporter expression may be associated with the alteration of miRNA expression. Therefore, this study investigated the impact of 19 xenobiotic drugs (e.g. dexamethasone, vinblastine, bilobalide and cocaine) on the expression of ten miRNAs (miR-18a, -27a, -27b, -124a, -148a, -324-3p, -328, -451, -519c and -1291) in MCF-7, Caco-2, SH-SY5Y and BE(2)-M17 cell systems. The data revealed that miRNAs were differentially expressed in human cell lines and the change in miRNA expression was dependent on the drug, as well as the type of cells investigated. Notably, treatment with bilobalide led to a 10-fold increase of miR-27a and a 2-fold decrease of miR-148a in Caco-2 cells, but no change of miR-27a and a 2-fold increase of miR-148a in MCF-7 cells. Neuronal miR-124a was generally down-regulated by psychoactive drugs (e.g. cocaine, methadone and fluoxetine) in BE(2)-M17 and SH-SY5Y cells. Dexamethasone and vinblastine, inducers of drug-metabolizing enzymes and transporters, suppressed the expression of miR-27b, -148a and -451 that down-regulate the enzymes and transporters. These findings should provide increased understanding of the altered gene expression underlying drug disposition, multidrug resistance, drug-drug interactions and neuroplasticity.

MicroRNA-328 negatively regulates the expression of breast cancer resistance protein (BCRP/ABCG2) in human cancer cells.

Breast cancer resistance protein (BCRP/ABCG2) is a molecular determinant of pharmacokinetic properties of many drugs in humans. To understand post-transcriptional regulation of ABCG2 and the role of microRNAs (miRNAs) in drug disposition, we found that microRNA-328 (miR-328) might readily target the 3'-untranslated region (3'-UTR) of ABCG2 when considering target-site accessibility. We then noted 1) an inverse relation between the levels of miR-328 and ABCG2 in MCF-7 and MCF-7/MX100 breast cancer cells and 2) that miR-328 levels could be rescued in MCF-7/MX100 cells by transfection with miR-328 plasmid. Luciferase reporter assays showed that ABCG2 3'-UTR-luciferase activity was decreased more than 50% in MCF-7/MX100 cells after transfection with miR-328 plasmid, the activity was increased over 100% in MCF-7 cells transfected with a miR-328 antagomir, and disruption of miR-328 response element within ABCG2 3'-UTR led to a 3-fold increase in luciferase activity. Furthermore, the level of ABCG2 protein was down-regulated when miR-328 was over-expressed, and the level was up-regulated when miR-328 was inhibited by selective antagomir. Altered ABCG2 protein expression was associated with significantly declined or elevated levels of ABCG2 3'-UTR and coding sequence mRNAs, suggesting possible involvement of the mechanism of mRNA cleavage. Finally, miR-328-directed down-regulation of ABCG2 expression in MCF-7/MX100 cells resulted in an increased mitoxantrone sensitivity, as manifested by a significantly lower IC(50) value (2.46 +/- 1.64 microM) compared with the control (151 +/- 32 microM). Together, these findings suggest that miR-328 targets ABCG2 3'-UTR and, consequently, controls ABCG2 protein expression and influences drug disposition in human breast cancer cells.

MicroRNAs regulate CYP3A4 expression via direct and indirect targeting.

CYP3A4 metabolizes many drugs on the market. Although transcriptional regulation of CYP3A4 is known to be tightly controlled by some nuclear receptors (NR) including vitamin D receptor (VDR/NR1I1), posttranscriptional regulation of CYP3A4 remains elusive. In this study, we show that noncoding microRNAs (miRNAs) may control posttranscriptional and transcriptional regulation of CYP3A4 by directly targeting the 3'-untranslated region (3'UTR) of CYP3A4 and indirectly targeting the 3'UTR of VDR, respectively. Luciferase reporter assays showed that CYP3A4 3'UTR-luciferase activity was significantly decreased in human embryonic kidney 293 cells transfected with plasmid that expressed microRNA-27b (miR-27b) or mouse microRNA-298 (mmu-miR-298), whereas the activity was unchanged in cells transfected with plasmid that expressed microRNA-122a or microRNA-328. Disruption of the corresponding miRNA response element (MRE) within CYP3A4 3'UTR led to a 2- to 3-fold increase in luciferase activity. Immunoblot analyses indicated that CYP3A4 protein was down-regulated over 30% by miR-27b and mmu-miR-298 in LS-180 and PANC1 cells. The decrease in CYP3A4 protein expression was associated with significantly decreased CYP3A4 mRNA levels, as determined by quantitative real-time PCR (qPCR) analyses. Likewise, interactions of miR-27b or mmu-miR-298 with VDR 3'UTR were supported by luciferase reporter assays. The mmu-miR-298 MRE site is well conserved within the 3'UTR of mouse, rat, and human VDR. Down-regulation of VDR by the two miRNAs was supported by immunoblot and qPCR analyses. Furthermore, overexpression of miR-27b or mmu-miR-298 in PANC1 cells led to a lower sensitivity to cyclophosphamide. Together, these findings suggest that CYP3A4 gene expression may be regulated by miRNAs at both the transcriptional and posttranscriptional level.

Haptoglobin-beta chain defined by monoclonal antibody RM2 as a novel serum marker for prostate cancer.

In our previous study, monoclonal antibody RM2, established toward the glycosyl epitope, reflected grade of malignancy of prostate cancer cells whereas RM2 reactivity to benign glands was negative or weak. RM2 reactivity was also detected in stroma, suggesting the glycoprotein RM2 recognizes could be released into the bloodstream. Then, we explored RM2 reactivity to sera of early prostate cancer. We compared RM2 reactivity to sera between 62 patients with early prostate cancer and 43 subjects with benign prostatic disease, and examined RM2 reactivity before and after radical prostatectomy in 15 patients by Western blotting. We also examined RM2 reactivity to sera of the other urogenital cancers. RM2 reactivity was significantly enhanced on a serum glycoprotein with molecular mass approximately 40 kDa, hereby termed GPX, in the patients with early prostate cancer when compared with those with benign prostatic disease (p < 0.0001). Setting an appropriate cutoff level, RM2 reactivity to GPX for detection of prostate cancer had sensitivity of 87% and specificity of 84%, respectively. Furthermore, the level of RM2 reactivity significantly decreased after radical prostatectomy (p = 0.006). However, increased RM2 reactivity to GPX was also observed in the other urogenital cancers. The proteomics approach identified GPX as haptoglobin-beta chain and RM2 showed preferential reactivity toward haptoglobin-beta chain derived from prostate cancer when compared with polyclonal anti-haptoglobin antibody. Haptoglobin-beta chain defined by RM2 is a novel serum marker that may be useful for detection of early prostate cancer when coupled with prostate-specific antigen because it is not specific to prostate cancer.

[Influence of expression of six transmembrane epithelial antigen of the prostate-1 on intracellular reactive oxygen species level and cell growth: an in vitro experiment].

OBJECTIVE: To investigate the STEAP1 gene function of the newly discovered gene six transmembrAne epithelial antigen of the prostate-1 (STEAP1). METHODS: Total RNA was obtained from human prostate cancer tissue and underwent PCR amplification. The full length of STEAP1 gene thus obtained was cloned. Mammalian expression vector pcDNA3. 1-STEAP1 was constructed and stably transfected into the human thyroid epithelial cells of the line FRTAP2320. A growth curve of the transfected cells was drawn. The intracellular reactive oxygen species (ROS) level was determined by flow cytometry (FC) with dichlorodihydrofluorescein diacetate (DCFHDA). RESULTS: The growth curve showed that the STEAP1 transfected cells grew faster than the control cells. FC showed that the fluorescence intensity of he intracellular ROS of the STEAP1 transfected cells was 42.13 +/- 1.13, significantly higher than those of the cell transfected with blank plasmid (10.02 +/- 1.42) and un-transfected cells (13.02 +/- 2.42, both P < 0.01). CONCLUSION: STEAP1 promotes the cell growth through inducing the intracellular ROS level.

[3,3-diindolylmethane enhances the inhibitory effect of idarubicin on the growth of human prostate cancer cells].

OBJECTIVE: To study the effects of idarubicin (IDA) combined with 3, 3-diindolylmethane (DIM) on the growth inhibition of human prostate cancer cells. METHODS: Human prostate cancer cells of the line PC-3M were cultured and then divided into the following groups: control group with solvent added into the culture fluid; IDA groups, with IDA of the terminal concentrations of 0.5, 1 or 5 mg/L added into the culture fluid; DIM groups, with DIM of the terminal concentrations of 30, 60 or 100 micromol/L added into the culture fluid; and DIM + IDA groups, with 0. 5 mg/L IDA and DIM 30, 60 or 100 micromol/L added into the culture fluid. 48 h later the cell growth inhibition rate was detected by MTT assay. Flow cytometry and acridine orange staining were used to detect the cell cycle and apoptosis. RT-PCR and Western blotting were used to detect the mRNA and protein expression of caspase 9, an apoptosis gene. RESULTS: Both IDA and DIM dose-dependently inhibited the growth of the PC-3M cells. The growth inhibition rate of the 60 micromol/L DIM + 0.5 mg/L IDA group was 69.9%, almost 10 times as that of the 0.5 mg/L IDA group. The apoptosis rate of the 60 micromol/L DIM + 0. 5 mg/L IDA group was 47.0%, significantly higher than that of the 0.5 mg/L IDA group (3.2%, P < 0.05). RT-PCR and Western blotting showed that the combination of DIM and IDA significantly enhanced the mRNA and protein expression of caspase 9. CONCLUSION: DIM enhances the growth inhibition effect of IDA on human prostate cancer cells by the mechanism of induction of apoptosis.

Predictive Performance of Physiologically-Based Pharmacokinetic Models in Predicting Drug-Drug Interactions Involving Enzyme Modulation.

BACKGROUND: Physiologically-based pharmacokinetic (PBPK) modeling in predicting metabolic drug-drug interactions (mDDIs) is routinely used in drug development. Currently, the US FDA endorses the use of PBPK to potentially support dosing recommendations for investigational drugs as enzyme substrates of mDDIs, and to inform a lack of mDDIs for investigational drugs as enzyme modulators. METHODS: We systematically evaluated the performance of PBPK modeling in predicting mDDIs published in the literature. Models developed to assess both investigational drugs as enzyme substrates (Groups 1 and 2, as being inhibited and induced, respectively) or enzyme modulators (Groups 3 and 4, as inhibitors and inducers, respectively) were evaluated. Predicted ratios of the area under the curve (AUCRs) and/or maximum plasma concentration (CmaxRs) with and without comedication were compared with the observed ratios. RESULTS: For Groups 1, 2, 3, and 4, 62, 50, 44, and 43% of model-predicted AUCRs, respectively, were within a predefined threshold of 1.25-fold of observed values (0.8-1.25x). When the threshold was widened to twofold, the values increased to 100, 80, 81, and 86% (0.5-2.0x). For Groups 3 and 4, prediction for mDDI liability (the existence or lack of mDDIs) using PBPK appears to be satisfactory. CONCLUSION: Our analysis supports the FDA's current recommendations on the use of PBPK to predict mDDIs.

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status.

A comprehensive search in literature and published US Food and Drug Administration reviews was conducted to assess whether physiologically based pharmacokinetic (PBPK) modeling could be prospectively used to predict clinical food effect on oral drug absorption. Among the 48 resulted food effect predictions, ∼50% were predicted within 1.25-fold of observed, and 75% within 2-fold. Dissolution rate and precipitation time were commonly optimized parameters when PBPK modeling was not able to capture the food effect. The current work presents a knowledgebase for documenting PBPK experience to predict food effect.

Application of surface-enhanced laser desorption/ionization time-of-flight-based serum proteomic array technique for the early diagnosis of prostate cancer.

AIM: To identify the serum biomarkers of prostate cancer (PCa) by protein chip and bioinformatics. METHODS: Serum samples from 83 PCa patients and 95 healthy men were taken from a mass screening in Changchun, China. Protein profiling was carried out using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). The data of spectra were analyzed using two bioinformatics tools. RESULTS: Eighteen serum differential proteins were identified in the PCa group compared with the control group (P < 0.01). There were four proteins at the higher serum level and 14 proteins at the lower serum level in the PCa group. A decision tree classification algorithm that used an eight-protein mass pattern was developed to correctly classify the samples. A sensitivity of 92.0% and a specificity of 96.7% for the study group were obtained by comparing the PCa and control groups. CONCLUSION: We identified new serum biomarkers of PCa. SELDI-TOF MS coupled with a decision tree classification algorithm will provide a highly accurate and innovative approach for the early diagnosis of PCa.

Predicting the Effect of CYP3A Inducers on the Pharmacokinetics of Substrate Drugs Using Physiologically Based Pharmacokinetic (PBPK) Modeling: An Analysis of PBPK Submissions to the US FDA.

BACKGROUND AND OBJECTIVE: We recently published analyses regarding the predictive performance of physiologically based pharmacokinetic (PBPK) models, submitted to the US Food and Drug Administration (FDA), for the effect of cytochrome P450 (CYP) inhibitors on the pharmacokinetics of substrate drugs. We now analyze and summarize the predictive performance of PBPK models for the effect of CYP3A inducers on a substrate's pharmacokinetics. METHODS: This analysis was based on 11 substrate PBPK models, developed by six sponsors, using a commercial PBPK software, with 13 clinical interaction studies. Four CYP3A inducers were used: rifampicin, rifabutin, carbamazepine, and efavirenz. Sponsors either directly used the software-provided inducer models or verified these models' induction magnitude prior to use. The metric for assessing predictive performance was the R predicted/observed value [R predicted/observed = (predicted mean exposure ratio)/(observed mean exposure ratio)], with the exposure ratio defined as maximum plasma concentration (C max) or area under the plasma concentration-time curve (AUC) with and without an inducer. RESULTS: In 77% (10/13; AUCR) and 83% (10/12; C max R) of the cases, the R predicted/observed values were within 1.25-fold of the observed data. Cases with R predicted/observed values >1.25-fold (>twofold for all three AUCR) were under-predictions as a result of using the PBPK software's default rifampicin model. Improved predictions were observed when the rifampicin model was modified by increasing the induction potency. CONCLUSION: Based on submissions to the FDA, and similar to our previous findings for CYP inhibition, we observed good agreement between PBPK-predicted and observed effect of CYP3A inducers on substrate pharmacokinetics. Verification of the inducer model appears to be crucial for improved predictive performance.

MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Better understanding of pancreatic cancer biology may help identify new oncotargets towards more effective therapies. This study investigated the mechanistic actions of microRNA-1291 (miR-1291) in the suppression of pancreatic tumorigenesis. Our data showed that miR-1291 was downregulated in a set of clinical pancreatic carcinoma specimens and human pancreatic cancer cell lines. Restoration of miR-1291 expression inhibited pancreatic cancer cell proliferation, which was associated with cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 sharply suppressed the tumorigenicity of PANC-1 cells in mouse models. A proteomic profiling study revealed 32 proteins altered over 2-fold in miR-1291-expressing PANC-1 cells that could be assembled into multiple critical pathways for cancer. Among them anterior gradient 2 (AGR2) was reduced to the greatest degree. Through computational and experimental studies we further identified that forkhead box protein A2 (FOXA2), a transcription factor governing AGR2 expression, was a direct target of miR-1291. These results connect miR-1291 to the FOXA2-AGR2 regulatory pathway in the suppression of pancreatic cancer cell proliferation and tumorigenesis, providing new insight into the development of miRNA-based therapy to combat pancreatic cancer.

The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives.

Transporters play an important role in drug absorption, disposition, and drug action. The evaluation of drug transporters requires a comprehensive understanding of transporter biology and pharmacology. Physiologically based pharmacokinetic (PBPK) models may offer an integrative platform to quantitatively evaluate the role of drug transporters and its interplay with other drug disposition processes such as passive drug diffusion and elimination by metabolizing enzymes. To date, PBPK modeling and simulations integrating drug transporters lag behind that for drug-metabolizing enzymes. In addition, predictive performance of PBPK has not been well established for predicting the role of drug transporters in the pharmacokinetics of a drug. To enhance overall predictive performance of transporter-based PBPK models, it is necessary to have a detailed understanding of transporter biology for proper representation in the models and to have a quantitative understanding of the contribution of transporters in the absorption and metabolism of a drug. This article summarizes PBPK-based submissions evaluating the role of drug transporters to the Office of Clinical Pharmacology of the US Food and Drug Administration.