Central venous catheter tip colonization and associated bloodstream infection in patients with severe burns under routine catheter changing.

BACKGROUND: Although routine changing of central venous catheters (CVCs) is commonly performed in patients with severe burns, information on pathogen colonization of the CVC tip and associated bloodstream infections (BSIs) is limited in those patients. METHODS: The medical records of 214 patients with severe burns who underwent routine CVC changing at 7-day intervals and their results of 686 pairs of CVC tips and concurrent blood cultures were retrospectively reviewed to evaluate the CVC colonization rate and associated BSI pathogens. RESULTS: Of the 686 CVCs, 137 (20.0%) were colonized by pathogens, and 81 (59.1%) of them had BSIs caused by the same pathogen. Nonflame burn (P = .002), total body surface area burn ≥30% (P = .004), femoral catheterization (P = .001), CVC changing during pre-existing BSI (P < .001), and renal replacement therapy (P = .017) were associated with catheter-related BSI in the multivariate analysis. Most BSIs were caused by Gram-negative bacteria (most commonly Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa). CONCLUSIONS: The CVC colonization rate in patients with severe burns and routine CVC changing was not high. Lengthening the CVC duration might be attempted in patients at a lower risk of catheter-related BSI although further prospective studies are necessary.

Pioneering predictions of AKI and AKIN severity in burn patients: a comprehensive CBC approach.

This study aims to evaluate the utility of complete blood count (CBC) markers, in conjunction with the acute kidney injury network (AKIN) criteria, for the early detection, severity assessment, and prediction of mortality outcomes of acute kidney injury (AKI) in burn patients. The research seeks to fill existing gaps in knowledge and validate the cost-effectiveness of using CBC as a routine diagnostic tool for better management of AKI. The study was conducted at Hangang Sacred Heart Hospital. We performed a large-scale retrospective analysis of 2758 adult patients admitted to the burn intensive care unit over a 12-year period. Among these patients, AKI occurred in 1554 patients (56.3%). Based on the AKIN stage classification, 794 patients (28.8%) were categorized as AKIN 1, 494 patients (17.9%) as AKIN 2, and 266 patients (9.6%) as AKIN 3. We defined several ratio markers, including the Neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR), Monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and various mean platelet volume (MPV) ratios. Our statistical analyses, conducted using the R programming language, revealed significant correlations between these markers and AKI severity. The AUC values for neutrophil count and WBC count were 0.790 and 0.793, respectively, followed by immature granulocyte count with an AUC of 0.727. For red blood cell (RBC)-related parameters, the AUC values for hematocrit (Hct), hemoglobin (Hb), and RBC count were 0.725, 0.713, and 0.713, respectively. Among the platelet-related parameters, only platelet distribution width (PDW) had an AUC of 0.677. Among the ratio markers, the NLR had the highest AUC at 0.772, followed by MPVNR and SII with AUC values of 0.700 and 0.680, respectively. The findings underscore the potential of CBC as an economical, routine test for AKI, thereby paving the way for enhanced patient outcomes. Our study suggests the utility of routine CBC tests, specifically WBC count and PLR, for predicting AKI and platelet, MPV, and NLR for mortality assessment in burn patients. These findings underscore the potential of easily accessible CBC tests in enhancing AKI management. However, further multicenter studies are needed for validation.

Big data insights into the diagnostic values of CBC parameters for sepsis and septic shock in burn patients: a retrospective study.

Sepsis and septic shock are prevalent and life-threatening complications in burn patients. Despite their severity, existing diagnostic methods are limited. This study aims to evaluate the efficacy of Complete Blood Count (CBC) and CBC ratio markers in diagnosing sepsis and septic shock, and in predicting mortality among burn patients. A cohort of 2757 burn patients was examined to ascertain the correlation between various CBC parameters, their ratios, and the incidence of sepsis and related mortality. Key markers analyzed included Red Cell Distribution Width (RDW), Mean Platelet Volume (MPV), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Mean Platelet Volume-to-Platelet Ratio (MPVPR). Our findings indicate that 65.5% of the patients developed sepsis, and 24.3% succumbed to their conditions. The CBC parameters RDW, MPV, NLR, MPVPR, and MPV-to-Lymphocyte Ratio (MPVLR) were significantly associated with sepsis and mortality. These markers showed considerable temporal variation and yielded an Area Under the Curve (AUC) of over 0.65 in an unadjusted Generalized Estimating Equations (GEE) model. This study underscores the potential of RDW, MPV, NLR, MPVPR, and MPVLR as vital prognostic tools for diagnosing sepsis, septic shock, and predicting mortality in burn patients. Although based on a single-center dataset, our results contribute to the enhancement of sepsis management by facilitating earlier, more precise diagnosis and treatment strategies. Further multi-center research is necessary to confirm these findings and broaden their applicability, establishing a solid base for future explorations in this crucial field.

Use of physiologically-based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended-release nifedipine.

Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well-understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The reported model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.

The clinical differentiation of blood culture-positive and -negative sepsis in burn patients: a retrospective cohort study.

Background: Sepsis is a potentially life-threatening condition that occurs when the body's response to infection leads to widespread inflammation and tissue damage. Negative cultures can make it difficult for clinicians to make a diagnosis and may raise questions about the validity of the definition of sepsis. In addition, the clinical distinctions between burn patients with blood culture-positive and -negative sepsis are also poorly understood. Therefore, this study aimed to examine the clinical differences between blood culture-positive and -negative sepsis in burn patients in order to improve the understanding of the pathophysiology and epidemiology of sepsis in this population. Methods: This study had a retrospective design, and the participants were adults aged ≥18 years. Patients diagnosed with sepsis were divided into two groups based on their blood culture results within 1 week of sepsis diagnosis. Results: We enrolled 1643 patients admitted to our institution's burn intensive care unit between January 2010 and December 2021. pH, platelet count, bicarbonate and haematocrit were significant in both the positive and negative groups. However, lymphocyte, red cell distribution width and blood urea nitrogen were significant only in the positive group, whereas lactate dehydrogenase was significant only in the negative group. Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumonia are common gram-negative bacterial species, and Staphylococcus aureus and Staphylococcus epidermidis are common gram-positive bacterial species seen in burn patients with positive blood cultures. Carbapenem resistance was found to be associated with an unfavourable prognosis in gram-negative bacteria, with the exception of P. aeruginosa. Conclusions: pH, platelet count, bicarbonate and haematocrit were routine biomarkers that demonstrated statistical significance in both groups. Lactate dehydrogenase was significant in the blood-negative group, while red cell distribution width, blood urea nitrogen and lymphocyte count were significant in the positive group. Furthermore, the most common causes of sepsis are gram-negative bacteria, including A. baumannii, K. pneumoniae and P. aeruginosa. Additionally, resistance to carbapenems is associated with unfavourable outcomes.

Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs.

One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and excipients from 16 putative BCS Class III drug substances in a total of 19 drug products via 133 approved abbreviated new drug applications (ANDAs) containing in vivo bioequivalence (BE) studies in human subjects during the time period from 2006 to 2022. We included the BCS Class III drugs in this study by referring to published literature, the World Health Organization (WHO) BCS Class I-IV list, FDA internal assessments, and physicochemical properties (high solubility and low permeability) of specific drug substances. Based upon all 133 approved generic formulations in this study, the highest amount of each different compendial excipient with a total of 40 is defined as its corresponding typical amount that has not shown any potential impact on in vivo drug absorption. In the present study, although only 30.08% of the investigated generic formulations met Q1 the same/Q2 similar formulation criteria for the BCS Class III biowaiver, and while approximately 69.92% failed to meet those criteria with non-Q1/Q2 similar formulations, all test/reference ratios (T/R) and 90% confidence intervals for all instrumental PK parameters (AUC0-t, AUC0-inf, and Cmax) met the bioequivalence (BE) criteria (80-125%). The results of formulation assessment suggest that the commonly used excipients without atypical amounts did not impact absorption of 16 putative BCS Class III drug substances. The rate and extent of absorption of drugs appears to be more dependent upon the biopharmaceutic and physiochemical properties of BCS Class III drug substance and less, or not dependent upon their formulations, excipients, and the excipients class. Our findings may lead to a more flexible formulation design space regarding the stringent BCS Class III formulation criteria.

Tracking longitudinal biomarkers in burn patients with sepsis and acute kidney injury: an unsupervised clustering approach.

BACKGROUND: Sepsis is a grave medical disorder characterized by a systemic inflammatory response to infection. Furthermore, it is a leading cause of morbidity and mortality, especially in hospitalized patients. Acute kidney injury (AKI) is a common complication of sepsis and is associated with increased morbidity and mortality. Patients with burns are particularly vulnerable to developing sepsis and AKI due to the extensive tissue damage and immune suppression resulting from burn injury. In this study, unsupervised clustering algorithms were used to track longitudinal biomarkers in patients with burns and assess their impact on mortality. METHODS: This retrospective study included adult patients with burns aged ≥ 18 years, who were admitted to the burn intensive care unit of Hallym University and Hangang Sacred Heart Hospital between July 2010 and December 2021. The patients were divided into two subgroups: those with sepsis (538 patients) and those without sepsis (826 patients). The longitudinal biomarkers were grouped into three clusters using the k-means clustering algorithm. Each cluster was assigned a letter from A to C according to its mortality rate. RESULTS: The odds ratio (OR) of pH was 9.992 in the positive group and 31.745 in the negative group in cluster C. The OR for lactate dehydrogenase (LD) was 3.704 in the positive group and 6.631 in the negative group in cluster C. The OR for creatinine was 2.784 in the positive group and 8.796 in the negative group in cluster C. The OR for blood urea nitrogen (BUN) in the negative group was 0.348, indicating a negative predictor of mortality. Regarding the application of Continuous Renal Replacement Therapy (CRRT) and ventilation, ventilation was significant in both groups. In contrast, CRRT application was not significant in the sepsis-positive group. Furthermore, it was not selected as a variable in the negative group. CONCLUSIONS: The pH, LD, and creatinine were significant in both groups, while lactate and platelets were significant in the sepsis-positive group. In addition, albumin, glucose, and BUN were significant in the sepsis-negative group. Continuous renal replacement therapy was not significant in either group. However, the use of a ventilator was associated with poor prognosis.

Evaluating clinical heterogeneity and predicting mortality in severely burned patients through unsupervised clustering and latent class analysis.

Burn injuries often result in a high level of clinical heterogeneity and poor prognosis in patients with severe burns. Clustering algorithms, which are unsupervised methods that can identify groups with similar trajectories in patients with heterogeneous diseases, can provide insights into the mechanisms of the disease pathogenesis. This study aimed to analyze routinely collected biomarkers to understand their mortality prediction power, identify the clinical meanings or subtypes, and inform treatment decisions to improve the outcomes of patients with burns. This retrospective cohort study included patients aged ≥ 18 years who were admitted between January 2010 and December 2021. The patients were divided into four subgroups based on the time period of their admission: week 1, 2, 3, and 4. The study revealed that 22 biomarkers were evaluated, and the red blood cell distribution width, bicarbonate level, pH, platelets, and lymphocytes were significantly associated with the mortality risk. Latent class analysis further demonstrated that the pH, platelets, lymphocytes, lactate, and albumin demonstrated the lowest levels in the cluster with the highest risk of mortality, with the lowest levels of pH and lactate being particularly noteworthy in week 1 of the study. During the week 2, the pH and lymphocyte levels were demonstrated to be significant predictors of the mortality risk, whereas the lymphocyte and platelet counts were meaningful predictors in week 3. During week 4, pH, platelet count, and albumin level were important predictors of mortality risk. Analysis of routinely collected biomarkers using clustering algorithms and latent class analysis can provide valuable insights into the heterogeneity of burn injuries and improve the ability to predict disease progression and mortality. Our findings suggest that lactate levels are a better indicator of cellular hypoxia in the early stages of burn shock, whereas platelet and lymphocyte levels are more indicative of infections such as sepsis. Albumin levels are considered a better indicator of reduced nutritional loss with decrease in unhealed burn wounds; however, the pH levels reflect the overall condition of the patient throughout the study period. These findings can be used to inform treatment decisions and improve the outcomes of burn patients.

The effect of food vehicles on in vitro performance of pantoprazole sodium delayed release sprinkle formulation.

Certain patient populations, including children, the elderly or people with dysphagia, find swallowing whole medications such as tablets and capsules difficult. To facilitate oral administration of drugs in such patients, a common practice is to sprinkle the drug products (e.g., usually after crushing the tablet or opening the capsule) on food vehicles before consumption which improves swallowability. Thus, evaluation of the impact of food vehicles on the potency and stability of the administered drug product is important. The aim of the current study was to evaluate the physicochemical properties (viscosity, pH, and water content) of common food vehicles used for sprinkle administration (e.g., apple juice, applesauce, pudding, yogurt, and milk) and their impacts on the in vitro performance (i.e., dissolution) of pantoprazole sodium delayed release (DR) drug products. The food vehicles evaluated exhibited marked difference in viscosity, pH and water content. Notably, the pH of the food as well as the interaction between food vehicle pH and drug-food contact time were the most significant factors affecting the in vitro performance of pantoprazole sodium DR granules. For example, the dissolution of pantoprazole sodium DR granules sprinkled on food vehicles of low pH (e.g., apple juice or applesauce) for short durations remained unchanged compared with the control group (i.e., without mixing with food vehicles). However, use of high pH food vehicles (e.g., milk) with prolonged contact time (e.g., 2 h) resulted in accelerated pantoprazole release, drug degradation and loss of potency. Overall, a thorough assessment of physicochemical properties of food vehicles and formulation characteristics are a necessary part of the development of sprinkle formulations.

Regulatory utility of physiologically-based pharmacokinetic modeling to support alternative bioequivalence approaches and risk assessment: A workshop summary report.

This report summarizes the proceedings for day 2 sessions 1 and 3 of the 2-day public workshop entitled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG). The aims of this workshop were: (1) to discuss how mechanistic modeling, including physiologically-based pharmacokinetic (PBPK) modeling and simulation, can support product development, and regulatory submissions; (2) to share the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (3) to establish a consensus on best practices for using PBPK modeling for BE assessment to help drive further investment by the generic drug industry into mechanistic modeling and simulation; and (4) to introduce the concept of a Model Master File to improve model-sharing. The theme of day 2 covered PBPK absorption model for oral products as an alternative BE approach and a tool for supporting risk assessment and biowaiver (session 1), oral PBPK for evaluating the impact of food on BE (session 2), successful cases, and challenges for oral PBPK (session 3). This report summarizes the topics of the presentations of day 2 sessions 1 and session 3 from FDA, academia, and pharmaceutical industry, including the current status of oral PBPK, case examples as well as the challenges and opportunities in this area. In addition, panel discussions on the utility of oral PBPK in both new drugs and generic drugs from regulatory and industry perspective are also summarized.

Application of Modeling and Simulation to Identify a Shortened Study Duration and Novel Bioequivalence Metric for a Long-Acting Intrauterine System.

An intrauterine system (IUS) can be implanted in the uterus and deliver drug directly at the site of pharmacological action. Mirena was the first FDA-approved levonorgestrel (LNG) releasing IUS without an approved generic form. Its 5-year application duration presents challenges for bioequivalence (BE) assessment using the conventional in vivo studies with pharmacokinetic and/or comparative clinical endpoints. Conventionally, along with other conditions, BE could be established if the 90% confidence interval (CI) of the ratio of geometric means of residual LNG at the end of 5 years is within the BE limits of 80.00% and 125.00%. Modeling and simulation were conducted to identify a shortened BE study duration and its corresponding BE acceptance limit that can be used as a surrogate for the conventional limit for a 5-year study. Simulation results suggest that having the 90% CI of the residual LNG 12 months post insertion within 95.00-105.26% would ensure that residual LNG amount at 5 years to be within 80.00-125.00%. This modeling and simulation practice leads to the current BE recommendation: if a test IUS is made of the same material in the same concentration and has the same physical dimensions as the Mirena, its BE could be established by showing (1) comparative physicochemical and mechanical properties; (2) comparative in vitro drug release behavior for 5 years; and (3) performance in a comparative short-term in vivo study and BE based on 90% confidence interval of test and reference ratio of residual LNG to be within 95.00-105.26% at month 12.

Reforming the countermeasures injury compensation program for COVID-19 and beyond: An economic perspective.

As of Aug. 2, 2021, 1693 injury claims associated with COVID-19 medical countermeasures have been filed in the Countermeasures Injury Compensation Program (CICP), of which 686 claims were related to COVID-19 vaccines and urgently needed compensation decisions. However, from an economic and public policy perspective, we find that the CICP design has unintended consequences: locating CICP in the executive agency DHHS potentially creates a conflict of interest, and not permitting judicial review generates a lack of checks and balances, both of which could jeopardize justice. These fundamental problems would subsequently weaken four key performance indicators of CICP compared with its judicial counterpart in the Court of Federal Claims. CICP lacks accountability, transparency, and cost-effectiveness efficiency, with 94% of its total costs spent on administration rather than compensation. CICP's ability to compensate is also questionable. If COVID-19 claims were compensated at its historical rate, CICP would face around $21.16 million in compensation outlays and $317.94 million in total outlays, 72.1 times its current balance. To ensure just compensation for injured petitioners during COVID-19 and future public health emergencies, we recommend Congress (1) initiate a major reform by relocating CICP from DHHS to the Claims Court or (2) keep CICP within DHHS and make incremental changes by permitting judicial review of DHHS administrative adjudication of CICP claims. We further recommend Congress audit and adjust budgets for CICP and DHHS promptly propose an injury table for COVID-19 claims. This is the first study that contributes an economic perspective to the limited literature on CICP and also provides unique and rich economic data.

Considerations for the Forced Expiratory Volume in 1 Second-Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1 ) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose-response relationship for most OIDPs. The utility of applying dose-scale analysis was also investigated by the FDA but often not recommended, due to either flat dose-response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost- and time-efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre-abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BACKGROUND: Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of "drug liking," "take drug again"), which are referred to as 'pharmacodynamic (PD)' responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs. METHODS: Extensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data. FINDINGS: Following oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65. INTERPRETATION: Our assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs. FUNDING: The study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Particle size affects pharmacokinetics of milled oxycodone hydrochloride tablet products following nasal insufflation in nondependent, recreational opioid users.

This study assessed the impact of product particle sizes (fine: 106-500 µm; coarse: 500-1000 µm) on oxycodone pharmacokinetics (PK) following nasal insufflation of milled oxycodone extended-release (ER) abuse-deterrent (AD) tablets using immediate-release (IR) non-AD product as reference. Additionally, this study assessed the effects of different excipient to drug ratio (EDR) by comparing two products with fine particle size but different EDRs, again using IR non-AD as the control. Thirty milligrams of oxycodone were administered in each treatment. Coarsely milled 30 mg ER tablets demonstrated significantly lower maximum plasma concentration (Cmax ) and partial areas under the concentration-time curve (AUCs) than those of the finely milled IR tablets. Finely milled ER tablets demonstrated similar Cmax and partial AUCs but higher total systemic exposures than those of finely milled IR tablets. Finely milled 80 mg ER tablets were bioequivalent to IR tablet on all parameters. The finely milled 30 mg ER tablet was not bioequivalent to the coarsely milled 30 mg ER tablet and had higher values for all parameters. The finely milled 30 mg ER tablets (EDR 6.9) showed no PK differences with finely milled 80 mg ER tablets (EDR 4.9). No serious adverse events were reported. The study demonstrated a significant effect of particle sizes (106-1000 µm) on PK of milled and insufflated oxycodone ER AD tablets. EDR difference did not have any significant effects on the PK of finely milled oxycodone ER AD tablets. Particle size distribution should be considered when nasal AD properties of opioid drug products are investigated during drug development.

Prognostic Value of Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA 19-9) in Gallbladder Cancer; 65 IU/mL of CA 19-9 Is the New Cut-Off Value for Prognosis.

Due to the lack of appropriate tumor markers with optimal cut-off values to predict the prognosis of gallbladder cancer (GBC), this study aimed to demonstrate the relationship between prognosis and the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), and to determine optimal thresholds. In total, 539 patients diagnosed with GBC were examined. The relationship between tumor marker levels and overall survival (OS) was analyzed. The C-tree method was used to suggest tumor marker thresholds, and multivariate analysis was conducted to identify prognostic factors for overall survival. The mean age of the patients was 65.3 years, and the 5-year overall survival rate in all patients was 68.9%. Following the C-tree method, the optimal cut-off value was set at 5 IU/mL for CEA and at 65 IU/mL for CA 19-9. Multivariate analysis revealed that age, CA 19-9 level, operative method, T stage, and N stage were significant prognostic factors for OS. Consequently, CA 19-9 had a stronger association with prognosis than CEA, and 65 IU/mL for CA 19-9 may be suggestive in evaluating the prognosis of GBC. Moreover, it could be an effective indicator for determining the surgical extent necessary and the need for adjuvant treatment.

Impact of Sex on Clinical Response in Rheumatoid Arthritis Patients Treated With Biologics at Approved Dosing Regimens.

The prevalence of rheumatoid arthritis (RA) is higher in females than in males. With the development of new treatment options and strategies such as biologics, we found it worthwhile to identify whether males and females warrant different treatment regimens to ensure the best clinical response. Our meta-analysis included 11 clinical trials of RA patients in support of the Food and Drug Administration's approval of 6 biological products. We evaluated the data of American College of Rheumatology 20 (ACR20) 24 or 26 weeks after treatment. Logistic regression models were applied to compute the odds ratio (OR) of treatment responses between sexes. The ORs of ACR20 response rates in males and females were similar across all studies and not significantly different in overall studies (OR, 1.05; 95% confidence interval, 0.96-1.16) analyzed with a fixed-effects model. Further analyses on the 7 ACR20 subcomponents showed high heterogeneity among studies (Q statistic P < .00007, I2 > 95%), with no observed clinically meaningful sex-related difference. Thus, our meta-analysis did not find significant difference in ACR20 response rates between male and female RA patients treated with biologics at approved dosing regimens. This result supports the current clinical practice of not requiring sex-dependent treatment regimens for RA patients.