Evaluating county-level lung cancer incidence from environmental radiation exposure, PM2.5, and other exposures with regression and machine learning models.

Characterizing the interplay between exposures shaping the human exposome is vital for uncovering the etiology of complex diseases. For example, cancer risk is modified by a range of multifactorial external environmental exposures. Environmental, socioeconomic, and lifestyle factors all shape lung cancer risk. However, epidemiological studies of radon aimed at identifying populations at high risk for lung cancer often fail to consider multiple exposures simultaneously. For example, moderating factors, such as PM2.5, may affect the transport of radon progeny to lung tissue. This ecological analysis leveraged a population-level dataset from the National Cancer Institute's Surveillance, Epidemiology, and End-Results data (2013-17) to simultaneously investigate the effect of multiple sources of low-dose radiation (gross [Formula: see text] activity and indoor radon) and PM2.5 on lung cancer incidence rates in the USA. County-level factors (environmental, sociodemographic, lifestyle) were controlled for, and Poisson regression and random forest models were used to assess the association between radon exposure and lung and bronchus cancer incidence rates. Tree-based machine learning (ML) method perform better than traditional regression: Poisson regression: 6.29/7.13 (mean absolute percentage error, MAPE), 12.70/12.77 (root mean square error, RMSE); Poisson random forest regression: 1.22/1.16 (MAPE), 8.01/8.15 (RMSE). The effect of PM2.5 increased with the concentration of environmental radon, thereby confirming findings from previous studies that investigated the possible synergistic effect of radon and PM2.5 on health outcomes. In summary, the results demonstrated (1) a need to consider multiple environmental exposures when assessing radon exposure's association with lung cancer risk, thereby highlighting (1) the importance of an exposomics framework and (2) that employing ML models may capture the complex interplay between environmental exposures and health, as in the case of indoor radon exposure and lung cancer incidence.

Comparative pharmacokinetic and bioequivalence evaluation of two formulations of morniflumate 350-mg tablets in healthy male subjects
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BACKGROUND: Morniflumate is a nonsteroid anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-1, 2 (COX-1, 2). OBJECTIVE: This study aimed to compare the pharmacokinetics (PKs) and assess the bioequivalence of two different formulations of morniflumate 350-mg tablets in healthy Korean male subjects. METHODS: A randomized, single-dose, two-period, two-sequence crossover study was conducted with 38 subjects. Subjects received a single dose of two tablets of either a test or a reference formulation and the alternated formulation in the next period. Serial blood samples for the PK analysis were collected over 12 hours. PK parameters were determined by a noncompartment analysis. PK parameters, including the maximum concentration (Cmax) and the area under-the-concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) were compared in bioequivalence tests. RESULTS: The Cmax of the test and reference formulations were 985.72 ± 6.80 mg/L and 947.09 ± 6.73 mg/L, respectively, while the AUClast values were 2675.92 ± 7.84 mg×h/L and 2653.06 ± 7.78 mg×h/L, respectively. The geometric mean ratios (90% confidence interval) of the test formulation to the reference formulation for Cmax and AUClast were 1.0715 (0.9469 - 1.2124) and 1.0592 (0.9592 - 1.1695), respectively. CONCLUSIONS: The new formulation of morniflumate 350-mg tablet showed a PK profile similar to that of the marketed formulation, and the results of this study fell within in the conventional criteria of bioequivalence.
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Evaluation of pharmacokinetic drug-drug interaction between tegoprazan and clarithromycin in healthy subjects.

Tegoprazan is a novel potassium-competitive acid blocker that treats gastric acid-related diseases. Clarithromycin was widely used as one of various regimens for eradicating Helicobacter pylori. This study compared the pharmacokinetic and safety profile of tegoprazan and clarithromycin between combination therapy and monotherapy to evaluate the potential drug-drug interaction. An open-label, randomized, 6-sequence, 3-period crossover study was conducted in 24 healthy subjects. According to the assigned sequence, the subject was administered the assigned treatment during 5 days in each period. PK parameters of tegoprazan and clarithromycin administered in combination were compared with those of the respective monotherapies. The co-administration of tegoprazan with clarithromycin increased maximum steady-state plasma concentration (Css,max) and area under the plasma concentration-time curve in dosing interval at steady-state (AUCss,tau) of tegoprazan (1.6-fold in Css,max and 2.5-fold in AUCss,tau) and M1 (2.0-fold in Css,max, 2.5-fold in AUCss,tau) than tegoprazan alone. The Css,max and AUCss,tau of 14-hydroxyclarithromycin increased 1.8- and 2.0-fold in co-administration, respectively. The AUCss.tau of clarithromycin was slightly increased in co-administration, but Css,max was not changed. Combination of tegoprazan and clarithromycin and those of the respective monotherapies were tolerated in 24 healthy subjects. There may exist drug interaction that lead to reciprocal increase in plasma drug concentrations when tegoprazan and clarithromycin were administrated in combination and no safety concerns were raised. It is suggested that an in-depth analysis of the concentration-response relationship is necessary to determine whether these concentration changes warrant clinical action. Trial Registration: ClinicalTrials.gov Identifier: NCT02052336.

Consecutive Ink Writing of Conducting Polymer and Graphene Composite Electrodes for Foldable Electronics-Related Applications.

For foldable electronic devices of the future, most components should have very good flexibility and reliability to maintain electrical properties even under repeated deformation. In this study, two types of inks for conducting polymer and graphene were simultaneously printed on flexible plastic substrates via the newly developed consecutive ink writing (CIW) process for the formation of composite electrodes of foldable electronic devices. To consecutively print conducting polymer ink and graphene ink, a conventional three-dimensional (3D) printer was modified by installing two needles in the printer head, and the two inks were printed through the nozzle in the same route with a time interval. By adjusting several printing conditions (ink concentration, printing parameters, printing time intervals between the two inks, etc.), various structures of composite electrodes, such as layered or fused 2D or 3D structures were developed on the glass substrate. Furthermore, by changing the printing order of the two inks and 3D printer bed temperature, the composite electrodes with a higher printing resolution were successfully printed on the flexible polyimide substrate. The printed composite electrodes via CIW process exhibit the lowest surface electrical resistance of 0.9 kΩ and high flexibility, and stable resistance values were maintained after 1000 cycles of the folding test. Consequently, the CIW process developed in this study applies to the production of the electrical parts and components for various flexible devices, such as foldable and wearable electronics.

Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects.

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.

Prediction of Drug-Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation.

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug-drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator® and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure.

Pharmacokinetics and Pharmacodynamics of Ursodeoxycholic Acid in an Overweight Population With Abnormal Liver Function.

Ursodeoxycholic acid (UDCA) is a secondary bile acid that is used to treat primary biliary cholangitis. Although UDCA has a hepatoprotective effect in some diseases, its benefit in nonalcoholic fatty liver disease (NAFLD) remains controversial. We aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of UDCA in overweight subjects with elevated liver enzymes after multiple administrations of UDCA and compare these changes with vitamin E treatment. Overweight subjects (body mass index, 25-30 kg/m2 ) with elevated alanine aminotransferase (ALT) level (40-200 IU/L) were enrolled. Subjects received one of the following three 8-week treatments: UDCA 300 mg twice daily UDCA 300 mg twice daily for 4 weeks followed by UDCA 300 mg twice daily and metformin 500 mg twice daily for 4 weeks, and vitamin E 400 IU twice daily. PK and PD (liver function, lipid profiles, insulin sensitivity, and miR-122) analyses were performed. Thirty subjects were enrolled; 1 subject withdrew his consent during the study. The PK characteristics were similar to those of healthy volunteers. The ALT and miR-122 levels decreased in the UDCA groups, whereas the ALT and aspartate aminotransferase levels decreased in the vitamin E group. The lipid profiles and insulin sensitivity did not show significant changes among the groups. There was no serious adverse event, and the safety profiles were similar among the treatment groups. The liver enzyme and miR-122 levels were decreased by UDCA. Considering UDCA and vitamin E have a hepatoprotective effect and different mechanisms of action, combination therapy could be an option for NAFLD.

Comparison of the Pharmacokinetics of a Fixed-Dose Combination of Rosuvastatin/Metformin Sustained-Release (10/1000 mg) and Separate Tablets in Healthy Male Subjects.

Fixed-dose combination (FDC) drugs with various dose combinations for the treatment of type 2 diabetes mellitus and dyslipidemia are currently in demand. We compared the pharmacokinetic (PK) profiles of the rosuvastatin/metformin sustained-release (10/1000 mg) FDC and separate tablets and evaluated the effect of food by randomized, open-label, 3-period, 6-sequence crossover studies conducted in healthy male subjects. Subjects were randomly assigned to one of the following treatments: separate tablets of 10 mg rosuvastatin and 1000 mg metformin sustained release in the fed state and the FDC in the fasted and fed states. PK samples were collected up to 72 hours postdose for rosuvastatin, N-desmethyl rosuvastatin, and metformin. The PK parameters were determined using a noncompartmental method, and the geometric mean ratio (GMR) and the 90% confidence interval (CI) of the treatments were calculated. A total of 35 subjects completed the study. The GMR and 90%CI of the peak concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the last measurable concentration (AUClast ) of the FDC and the separate tablets were within the bioequivalence criteria (0.8-1.25) for both rosuvastatin and metformin. The effect of food was statistically significant for both rosuvastatin and metformin but not expected to be of clinical significance.

Tissue pharmacokinetics of DHP107, a novel lipid-based oral formulation of paclitaxel, in mice and patients by positron emission tomography.

DHP107 is a newly developed lipid-based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope-labeled [3 H]DHP107 and [18 F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107. In vivo tissue PK were assessed in healthy ICR mice and breast cancer xenografted SCID mice. Two patients with metastatic breast cancer were clinically evaluated for absorption at the target lesion after internal absorbed dose estimation. Whole-body PET/computed tomography data were acquired in healthy and xenografted mice and in patients up to 10-24 h after administration. Tissue [18 F]DHP107 signals were plotted against time and PK parameters were determined. The amounts of radioactivity in various organs and excreta were determined using a beta-counter and are expressed as the percentage of injected dose (ID). Oral [18 F]DHP107 was well-absorbed and reached the target lesion in mice and patients with breast cancer. Significant amounts of radioactivity were found in the stomach, intestine, and liver after oral administration of [3 H]- and [18 F]DHP107 in healthy mice. The [18 F]DHP107 reached a peak distribution of 0.7-0.8%ID in the tumor at 5.6-7.3 h in the xenograft model. The [18 F]DHP107 distribution in patients with metastatic breast cancer was the highest at 3-4 h postadministration. Systemic exposures after administration of a DHP107 therapeutic dose were comparable with those in previous studies. PET using radioisotope-labeled drug candidates is useful for drug development and can provide valuable information that can complement plasma PK data, particularly in early phase clinical trials.

Use of Molecular Imaging in Clinical Drug Development: a Systematic Review.

BACKGROUND: Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can provide the crucial pharmacokinetic-pharmacodynamic information of a drug non-invasively at an early stage of clinical drug development. Nevertheless, not much has been known how molecular imaging has been actually used in drug development studies. METHODS: We searched PubMed using such keywords as molecular imaging, PET, SPECT, drug development, and new drug, or any combination of those to select papers in English, published from January 1, 1990, to December 31, 2015. The information about the publication year, therapeutic area of a drug candidate, drug development phase, and imaging modality and utility of imaging were extracted. RESULTS: Of 10,264 papers initially screened, 208 papers met the eligibility criteria. The more recent the publication year, the bigger the number of papers, particularly since 2010. The two major therapeutic areas using molecular imaging to develop drugs were oncology (47.6%) and the central nervous system (CNS, 36.5%), in which efficacy (63.5%) and proof-of-concept through either receptor occupancy (RO) or other than RO (29.7%), respectively, were the primary utility of molecular imaging. PET was used 4.7 times more frequently than SPECT. Molecular imaging was most frequently used in phase I clinical trials (40.8%), whereas it was employed rarely in phase 0 or exploratory IND studies (1.4%). CONCLUSIONS: The present study confirmed the trend that molecular imaging has been more actively employed in recent clinical drug development studies although its adoption was rather slow and rare in phase 0 studies.

Pharmacokinetic comparison between fixed-dose combination of fimasartan/amlodipine 60/10 mg and the corresponding loose combination through partial replicated crossover study in healthy subjects.

Combination therapies of antihypertensive drugs are recommended in cases where hypertension is not controlled by monotherapy. This study aimed to compare the pharmacokinetics (PKs) between fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg and the corresponding loose combination. Because of the high intra-subject variability for maximum plasma concentration (Cmax) of fimasartan, a randomized, open-label, 3×3 partial replicated crossover design was adopted. Subjects received a single dose of FDC of fimasartan/amlodipine 60/10 mg or the corresponding loose combination in each period. Blood samples for PK analysis were collected up to 48 hours for fimasartan and 144 hours for amlodipine, respectively. Geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) of the FDC to the loose combination for Cmax and area under the concentration-time curve from time 0 to the last quantifiable time point (AUClast) were calculated. Sixty healthy subjects were randomized, and 57 subjects completed the study. The concentration-time profiles of fimasartan and amlodipine were similar between the FDC and loose combination. The GMRs (90% CIs) of the FDC to the loose combination for Cmax and AUClast were 1.0440 (0.9202-1.1844) and 1.0412 (0.9775-1.1090) for fimasartan, and 1.0430 (1.0156-1.0711) and 1.0339 (1.0055-1.0631) for amlodipine, respectively. The GMRs and its 90% CIs for Cmax and AUClast of fimasartan and amlodipine were included not only in the scaled bioequivalence criteria but also in the conventional bioequivalence criteria. In conclusion, FDC of fimasartan/amlodipine 60/10 mg showed comparable PK profiles with the corresponding loose combination, which suggests their bioequivalence.

Failure mode and effects analysis drastically reduced potential risks in clinical trial conduct.

BACKGROUND: Failure mode and effects analysis (FMEA) is a risk management tool to proactively identify and assess the causes and effects of potential failures in a system, thereby preventing them from happening. The objective of this study was to evaluate effectiveness of FMEA applied to an academic clinical trial center in a tertiary care setting. METHODS: A multidisciplinary FMEA focus group at the Seoul National University Hospital Clinical Trials Center selected 6 core clinical trial processes, for which potential failure modes were identified and their risk priority number (RPN) was assessed. Remedial action plans for high-risk failure modes (RPN >160) were devised and a follow-up RPN scoring was conducted a year later. RESULTS: A total of 114 failure modes were identified with an RPN score ranging 3-378, which was mainly driven by the severity score. Fourteen failure modes were of high risk, 11 of which were addressed by remedial actions. Rescoring showed a dramatic improvement attributed to reduction in the occurrence and detection scores by >3 and >2 points, respectively. CONCLUSIONS: FMEA is a powerful tool to improve quality in clinical trials. The Seoul National University Hospital Clinical Trials Center is expanding its FMEA capability to other core clinical trial processes.

LBEC0101, A Proposed Etanercept Biosimilar: Pharmacokinetics, Immunogenicity, and Tolerability Profiles Compared with a Reference Biologic Product in Healthy Male Subjects.

OBJECTIVES: We performed this study to compare the pharmacokinetic (PK), immunogenicity, and tolerability profiles of etanercept between LBEC0101, a proposed biosimilar, and Enbrel®, the reference biological product. METHODS: A randomized, double-blind, single-dose, two-treatment, two-period, two-sequence, crossover study was conducted in 48 healthy males. In each period, a single dose of LBEC0101 or Enbrel® was subcutaneously injected at 25 mg and serial blood samples for PK evaluation were collected up to 648 h post-dose. Serum etanercept concentrations and anti-drug antibodies (ADA) were measured using an enzyme-linked immunosorbent assay and an affinity capture elution assay. Log-transformed maximum concentration (C max) and area under the concentration-time curve (AUCinf) were compared. Tolerability was also evaluated. RESULTS: The serum concentration-time profiles were almost overlapped between LBEC0101 and Enbrel®. Geometric mean ratio (90% confidence intervals) for C max and AUCinf of LBEC0101 to Enbrel® were 1.02 (0.92-1.13) and 0.96 (0.87-1.05), respectively, which were within a conventional bioequivalence criteria of 0.80-1.25. ADA development was also comparable. Both drugs were well tolerated. CONCLUSIONS: LBEC0101 showed similar PK, immunogenicity, and tolerability profiles to Enbrel® after a single subcutaneous injection in healthy males. LBEC0101 can be further developed as a potential etanercept biosimilar (ClinicalTrial.gov identifier: NCT01725620).