Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz). MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for Cmax and AUC0-t were calculated to evaluate pharmacokinetic equivalence. RESULTS: The 90% CIs of the geometric mean ratios of Cmax and AUC0-t for tofacitinib free base to tofacitinib citrate were 0.9144 - 1.1230 and 1.0245 - 1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events. CONCLUSION: In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.

A combined web based intervention and ecological momentary intervention for reducing alcohol use among incoming first-year university students: Results from a three-arm randomised controlled trial.

BACKGROUND: The transition from high school to university is associated with increased alcohol use and harm. Web-based interventions (WBIs) and ecological momentary interventions (EMIs) are two methods that have had some success in reducing alcohol use among university students and may be particularly effective if implemented during the transition to university. The aim of the current study was to investigate the effectiveness of a combined WBI and EMI to reduce alcohol use among incoming university students. METHODS: Incoming first-year students (n = 783, in 2018 and 2019) were randomized into either a WBI + EMI, WBI-only, or an assessment-only condition. All participants completed online questionnaires before university, after their first and second semester, and reported their alcohol use fortnightly throughout their first year. Those in the WBI + EMI and WBI conditions received online feedback about their drinking (i.e., the WBI) immediately following the pre-university survey. Those in the WBI + EMI were also sent eight EMI messages to their mobile phones during Orientation Week and six EMI messages across the academic year aimed at reducing alcohol harm. RESULTS: There were no significant differences between the conditions in Orientation Week drinking, academic year drinking (both "typical" semester or fortnightly drinking), or alcohol-related harms. CONCLUSION: A WBI + EMI intervention aimed at the transition to university did not reduce university students' alcohol use. The transition, however, continues to be a period of serious harm where students drink more than any other period.

Understanding Aotearoa New Zealand University Students Intentions to Seek Help If Experiencing Mental Distress: A Comparison of Naturalistic and Interventional Findings.

University students globally are consistently identified as a vulnerable group for mental distress and suicide. Despite this, students report low engagement in help-seeking behaviours. This series of studies aimed to assess barriers to help-seeking for students and the impact of an intervention that sought to increase support-seeking intentions. In Study 1, 373 undergraduate psychology students completed items related to depression, anxiety, suicidal ideation, stigma, and help-seeking intentions. In Study 2, 133 undergraduate psychology students were randomly allocated into one of three intervention groups (control, infographic, video) and completed measures as used in Study 1. Despite experiencing clinically relevant symptoms and recent suicidal ideation, students in Study 1 tended to report low intentionality to seek help, citing perceptions that their distress was not serious enough or a desire to handle their issues independently. In Study 2, an infographic about different support services increased student's intentions to access support services and reduced their perception that their issues were not serious enough. Overall, Aotearoa New Zealand students endorsed similar barriers to help-seeking as students in other countries. Importantly, we demonstrated that a simple infographic intervention reduced perceptions regarding these common barriers and may increase students' knowledge about when to seek help.

A Content Analysis of Reddit Users' Perspectives on Reasons for Not Following Through with a Suicide Attempt.

Despite a growing understanding of the triggers for suicidal thoughts and behavior, little is known about the mechanisms that prevent people from killing themselves. The goal of the present study was to use publicly available Reddit data to better understand the reasons that people give for not following through with a potentially lethal suicide attempt. Threads containing key terms (e.g., "kill yourself") within the subreddit /r/AskReddit were collected and all top posts from these threads were thematically coded. Across the posts collected, 11 different themes were identified; friends and family, curiosity and optimism about the future, spite, purpose, transience, hobbies, animals/pets, fear of survival, fear of pain, death and/or the afterlife, apathy/laziness, and intervention. Some additional themes were captured in an "other" category, and a twelfth theme, use of pharmaceutical drugs, was identified, but not discussed. These findings provide a broad overview about the proximal protective factors that directly stopped people from making a suicide attempt. They also illustrate the potential for Reddit as platform through which to better understand factors that may help to identify and support those in suicidal crisis. Such insight may help to inform intervention and prevention strategies for suicide and those in suicidal crisis.

Multiple-dose pharmacokinetics and safety of amoxicillin/clavulanate in healthy elderly subjects.

BACKGROUND: Amoxicillin/clavulanate is a widely used oral formulation of penicillin combined with a ß-lactamase inhibitor. When using amoxicillin/clavulanate in the elderly, the risk of adverse drug reaction may be greater. This study aimed to evaluate the pharmacokinetics (PKs) and safety of multiple-dose amoxicillin/clavulanate administration in healthy elderly subjects and to compare the observed PK profiles with those in healthy younger adults. An open-label, one-sequence, multiple administration study was conducted in 16 healthy elderly subjects. MATERIALS AND METHODS: Subjects orally received amoxicillin and clavulanate 750/187.5 twice daily for 9 days. For PK analysis, serial blood samples were collected up to 12 hours after the last administration of amoxicillin/clavulanate. The demographic and PK data of this study were compared to those of healthy young adults from a separate study with a similar design. Safety assessments including clinical laboratory tests, physical examination, vital signs, and adverse event (AE) monitoring were performed throughout the study. RESULTS: All AEs were mild, and no serious AEs were reported in this study. The systemic exposure of amoxicillin and clavulanate was ~ 90% and 60% higher, respectively, in the elderly subjects than in the younger subjects. However, the time required to reach maximum concentration at steady state and the elimination half-life were similar in the two age groups. CONCLUSION: Although multiple administration of amoxicillin/clavulanate 750/187.5 mg was safe and well-tolerated, the systemic exposure of amoxicillin and clavulanate was higher in elderly subjects than in younger subjects.

Altered Gene Expression Profiles in Peripheral Blood Mononuclear Cells in Obese Subjects.

INTRODUCTION: Gene expression profiles in human peripheral blood mononuclear cells (PBMCs) may act as a useful tool to better understand obesity. We investigated gene expression levels in PMBCs for possible differences between obese and non-obese subjects (19-55 years) and evaluated correlations between gene expression in PBMCs and clinical obesity indices. METHODS: Body weight, BMI, fat amount, fat percentage, waist/hip ratio, leptin, and adiponectin levels were determined in 30 obese and 20 non-obese subjects. Expression levels of 19 genes, which were differentially expressed by clinical obesity indices in the PBMCs of high fat-fed rats, were determined in their PBMCs using real-time PCR. RESULTS: The expression of 9 of 19 previously selected genes was significantly correlated with one or more clinical obesity indices. Both TFEC and CCL2 expression were negatively correlated with BMI, fat amount, fat percentage, waist/hip ratio, and leptin concentration. Similarly, TNFAIP2, VCAN, ASSI, IRF1, and HK3 expression negatively correlated with some clinical obesity indices, such as TNFAIP2 for BMI, fat amount, fat percentage, and waist/hip ratio, VCAN for fat amount, fat percentage, and waist/hip ratio, ASS1 for BMI and fat amount, IRF1 for BMI, fat amount, and fat percentage, and HK3 for fat amount. In contrast, both TNF-α and LPL expression were positively correlated with waist/hip ratio. CONCLUSION: We identified 9 of 19 genes in human PBMCs that significantly correlated with one or more clinical obesity indices. Because these genes have a mechanistic basis for the development or progression of obesity and its metabolic derangements, they may help to determine possible underlying mechanisms for obesity.

Evaluation of the Pharmacokinetic Interaction Between Lobeglitazone and Dapagliflozin at Steady State.

PURPOSE: Coadministration of lobeglitazone and dapagliflozin is expected to result in a blood glucose-lowering effect, followed by a gradual increase, in clinical usage; however, combining drugs could cause negative interactions. This study aimed to evaluate the effect of the coadministration of lobeglitazone and dapagliflozin on their individual pharmacokinetic properties at steady state in healthy male volunteers in the fasted state. METHODS: This study consisted of 2 parts, each of which was a randomized, open-labeled, multiple-dose, 2-way crossover study in 20 healthy male volunteers in each part. Blood samples were taken periodically over a 48-h period after dosing to derive total plasma lobeglitazone and dapagliflozin pharmacokinetic properties; safety profile was evaluated throughout the study. FINDINGS: When the pharmacokinetic properties of dapagliflozin were evaluated following its administration alone and in combination with lobeglitazone, point estimate and 90% CI of the geometric mean ratio of dapagliflozin AUCτ were entirely within the conventional bioequivalence range of 80%-125%. However, although it was not clinically meaningful, its Css,max was ~8% lower in subjects receiving multiple doses of dapagliflozin and lobeglitazone than that in those administered dapagliflozin alone. The pharmacokinetic properties of lobeglitazone were evaluated following its administration alone and in combination with dapagliflozin. The geometric mean ratios and 90% CIs of the lobeglitazone Css,max and AUCτ were within the conventional bioequivalence range of 80%-125%. IMPLICATIONS: Coadministration of lobeglitazone and dapagliflozin had no apparent clinically relevant effects on the pharmacokinetic properties of either drug. Based on these findings, it is anticipated that lobeglitazone and dapagliflozin can be coadministered without dose adjustment. ClinicalTrials.gov identifier: NCT03616392.

Pharmacokinetic interactions between telmisartan/amlodipine and rosuvastatin after multiple oral administrations in healthy Korean male subjects.

PURPOSE: Hypertension and dyslipidemia are major risk factors for cardiovascular diseases, and reduction of cardiovascular risks can be achieved by combining antihypertensive therapy with statins. The objective of this study was to evaluate the pharmacokinetic interaction between telmisartan/amlodipine fixed dose combination and rosuvastatin in healthy Korean male volunteers. PATIENTS AND METHODS: An open-label, two-cohort, multiple-dose, single-sequence crossover study was conducted in healthy male subjects. In Cohort 1, the subjects were administered one tablet of telmisartan/amlodipine 80 mg/5 mg once daily for 14 days with or without one tablet of rosuvastatin 20 mg once daily. In Cohort 2, the subjects were administered one tablet of rosuvastatin 20 mg once daily for 14 days with or without one tablet of telmisartan/amlodipine 80 mg/5 mg once daily. Serial blood samples were collected up to 24 hrs post-dose on the 9th and 14th days in Cohort 1 and on the 5th and 14th days in Cohort 2. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration versus time curve over dosing interval (AUCτ,ss), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of log-transformed Cmax,ss and AUCτ,ss for separate or concurrent therapy were calculated to evaluate pharmacokinetic interactions. RESULTS: Thirty-eight subjects from Cohort 1 and nineteen subjects from Cohort 2 completed the study. The GLSM ratios and 90% CIs of Cmax,ss and AUCτ,ss, were 0.9829 (0.8334-1.1590) and 1.0003 (0.9342-1.0710) for telmisartan; 0.9908 (0.9602-1.0223) and 1.0081 (0.9758-1.0413) for amlodipine; and 2.2762 (2.0113-2.5758) and 1.3261 (1.2385-1.4198) for rosuvastatin, respectively. CONCLUSION: The pharmacokinetic parameters of telmisartan/amlodipine, but not rosuvastatin, met the pharmacokinetic equivalent criteria. The increase in systemic exposure to rosuvastatin caused by telmisartan/amlodipine co-administration would not be clinically significant in practice. Nevertheless, an appropriately designed two-sequence crossover study is needed to confirm the results of this study.

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.

Dose-proportional pharmacokinetic properties of GLA5PR GLARS-NF1 controlled-release pregabalin in healthy Korean volunteers: a randomized, open, single-dose, parallel study.

PURPOSE: The aim of this study was to evaluate the dose-proportional pharmacokinetic characteristics of pregabalin following the administration of GLA5PR GLARS-NF1 tablets (150, 300, 450, and 600 mg) in the fed state. SUBJECTS AND METHODS: An open-label, randomized, single-dose, parallel study was conducted in 40 eligible subjects who were randomly assigned to receive a single 150, 300, 450, or 600 mg dose of GLA5PR GLARS-NF1. Serial blood samples were collected before and after dosing for 36 hours, and plasma concentrations were determined using liquid chromatography-tandem mass spectrometry. Safety profiles were evaluated throughout the study (trial registration number: NCT02327000). RESULTS: Thirty-seven subjects completed the studies. The area under the plasma concentration-time curve up to the last measurable concentration of pregabalin exhibited dose proportionality following administration of GLA5PR GLARS-NF1 tablets from 150 to 600 mg while its maximum plasma concentration showed dose proportionality at a dose range of 150-450 mg. The safety evaluations showed no clinically significant finding after administration of GLA5PR GLARS-NF1 tablets (150, 300, 450, and 600 mg) in the fed state. CONCLUSIONS: The dose-proportional properties of GLA5PR GLARS-NF1 150-450 mg tablets were determined.

Effectiveness of a Combined Web-Based and Ecological Momentary Intervention for Incoming First-Year University Students: Protocol for a 3-Arm Randomized Controlled Trial.

BACKGROUND: Alcohol use among university students is common, and those who drink often choose to drink heavily (ie, 4 or more drinks per session for women or 5 or more for men). Web-based interventions (WBIs), in which students complete assessments and receive personalized feedback about their alcohol use, and ecological momentary interventions (EMIs), which use mobile devices as a method of delivering intervention information, are 2 methods that have had some success in reducing alcohol use among university students. OBJECTIVE: The aim of this study was to investigate the effectiveness of a combined WBI and EMI intervention to reduce alcohol use among university students. METHODS: The study is a 3-arm randomized controlled trial. Participants will be randomized into either a WBI+EMI condition, a WBI-only condition, or an assessment-only control. Our sample will consist of first-year university students, recruited through 5 residential colleges at the University of Otago, New Zealand. All participants will complete an online survey at baseline (ie, before Orientation Week); those in the WBI-only and WBI+EMI conditions will immediately receive personalized feedback (ie, the WBI), whereas participants in the assessment-only condition will receive no feedback. In addition, participants randomized into the WBI+EMI, but not those in the WBI-only or assessment-only groups, will receive 8 Orientation Week (2 per day on nights with large social events) and 6 academic year EMIs (delivered fortnightly). Participants in all conditions will complete brief surveys at the end of the first and second semester and report their weekend alcohol use fortnightly throughout each semester via ecological momentary assessments. RESULTS: The primary hypothesis is that participants in the WBI+EMI group will consume significantly fewer drinks during weekends in their first semester at university compared with WBI-only and assessment-only groups. Secondary hypotheses are that, when compared with the WBI-only and assessment-only groups, the WBI+EMI group will report consuming fewer drinks during Orientation Week, report experiencing fewer negative alcohol-related consequences after first semester, and report lower Alcohol Use Disorder Identification Test-Consumption scores following their first semester. CONCLUSIONS: This study adds to a growing body of work investigating the utility of WBIs and EMIs in curbing alcohol consumption. In addition, the study will help to inform policy approaches aimed at curbing alcohol consumption and alcohol-related harm in university students. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000015246; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374104&isReview=true (Archived by WebCite at http://www.webcitation.org/6z9jRLTz6). REGISTERED REPORT IDENTIFIER: RR1-10.2196/10164.

Safety, Tolerability, and Pharmacokinetic Characteristics of a Novel Nonopioid Analgesic, VVZ-149 Injections in Healthy Volunteers: A First-in-Class, First-in-Human Study.

VVZ-149, a dual antagonist of GlyT2 and 5HT2 A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early-stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single- and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0.25-8 mg/kg VVZ-149 or placebo in the SAD study (n = 46) or a 4-hour intravenous infusion of 4-7 mg/kg VVZ-149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ-149 and its active metabolite (VVZ-368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ-149 and VVZ-368 showed a dose-proportional increase. VVZ-149 did not accumulate in the plasma, whereas the plasma concentration of VVZ-368 increased by 1.23- to 2.49-fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single- or multiple-dose administration of VVZ-149 was generally well tolerated. These results showed that 0.5-8 mg/kg VVZ-149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies.

Quantitative analysis of acetylsalicylic acid in human blood using volumetric absorptive microsampling.

Volumetric absorptive microsampling (VAMS) is a novel sampling technique that allows for the collection of an accurate volume of blood by dipping a microsampler tip. The purpose of this study is to compare the requirement of a stabilizing reagent for the conventional venous blood sampling method versus VAMS in the analytical measurement of the concentration of acetylsalicylic acid. A high-performance liquid chromatography with mass spectrometry (LC-MS/MS) method was developed and validated for the accurate determination of acetylsalicylic acid in human blood. The blood samples spiked with acetylsalicylic acid with and without stabilizing reagent were absorbed into VAMS tips. In the whole blood sample, the same concentration was shown regardless of the addition of the stabilizing reagent, but the concentration decreased when the stabilizing reagent was not added to the VAMS sample. To apply the VAMS technology as a new blood sampling method, stabilizing reagents should be added before the analysis of acetylsalicylic acid concentration.

The first step to the powers for clinical trials: a survey on the current and future Clinical Trial Management System.

A clinical trial management system (CTMS) is a comprehensive program that supports an efficient clinical trial. To improve the environment of clinical trials and to be competitive in the global clinical trials market, an advanced and integrated CTMS is necessary. However, there is little information about the status of CTMSs in Korea. To understand the utilization of current CTMSs and requirements for a future CTMS, we conducted a survey on the subjects related to clinical trials. The survey was conducted from July 27 to August 16, 2017. The total number of respondents was 596, and 531 of these responses were used. Almost half of the respondents were from hospitals (46%). The proportion of respondents who are currently using a CTMS was the highest for contract research organizations at 59%, whereas the proportion used by investigators was 39%. The main reason for not using a CTMS was that it is unnecessary and expensive, but it showed a difference between workplaces. Many respondents frequently used CTMSs to check the clinical trial schedule and progress status, which was needed regardless of workplace. While two-thirds of users tended to be satisfied with their current CTMS, there were many users who felt their CTMS was inconvenient. The most requested function for a future CTMS was one that could be used to manage the project schedule and subject enrollment status. Additionally, a systematic linkage to electronic medical records, including prescription and laboratory test results, and a function to confirm the participation history of subjects in other hospitals were requested.

Safety, tolerability and pharmacokinetics of 21 day multiple oral administration of a new oxazolidinone antibiotic, LCB01-0371, in healthy male subjects.

BACKGROUND: LCB01-0371 is a new oxazolidinone antibiotic, which targets most Gram-positive organisms. High rates of adverse reactions including myelosuppression have been reported for existing oxazolidinones, limiting their long-term use. OBJECTIVES: The safety, tolerability and pharmacokinetics (PK) of 21 day multiple oral administrations of LCB01-0371 in healthy male subjects (clinicaltrials.gov: NCT02540460) were investigated. METHODS: In this randomized, double-blind, placebo-controlled study, subjects received 800 mg of LCB01-0371 once or twice daily or 1200 mg of LCB01-0371 twice-daily for 21 days in a fasting state. Safety and tolerability profiles including laboratory tests were evaluated during the study and on a post-study visit and the results were analysed using repeated-measures analysis of variance (RM-ANOVA). Serial blood samples for PK analysis were collected up to 12 h after dosing on day 21. RESULTS: A total of 40 subjects were enrolled and 34 subjects completed the study. Two subjects dropped out according to stopping rules. In the 1200 mg twice-daily dose group, the absolute value of red blood cell count, haematocrit and haemoglobin decreased by 500 × 106/L (6.5%), 4.5% (6.8%) and 1.6 g/dL (6.9%), respectively, after 21 day administrations of LCB01-0371. However, mean relative changes from baseline of all haematology values were not significantly different among doses, including placebo (all, P < 0.05). PK profiles of LCB01-0371 in the dose range of 800 mg once daily to 1200 mg twice daily were consistent with previous studies. CONCLUSIONS: LCB01-0371 is well tolerated in healthy male subjects with comparable haematology profiles to placebo, after multiple doses of up to 1200 mg twice daily for 21 days.

Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers.

This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).

Effects of dexamethasone coadministered with oseltamivir on the pharmacokinetics of oseltamivir in healthy volunteers.

PURPOSE: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. METHODS: An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg) was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg) was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography-tandem mass spectrometry. RESULTS: Area under the plasma concentration-time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. The geometric mean ratio (90% confidence interval) of the metabolic ratio (oseltamivir carboxylate AUC0-48h/oseltamivir AUC0-48h) was 0.92 (0.87-0.97). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatments. CONCLUSION: Coadministration of dexamethasone with oseltamivir slightly decreased systemic exposure to oseltamivir and oseltamivir carboxylate in healthy volunteers. This result suggests that CES1 is inhibited by dexamethasone in humans. However, coadministration of oseltamivir and dexamethasone did not appear to have a clinically relevant effect on the PK of oseltamivir; based on these results, dexamethasone can be coadministered with oseltamivir.

Pharmacokinetic and bioequivalence study comparing a candesartan cilexetil/rosuvastatin calcium fixed-dose combination with the concomitant administration of candesartan cilexetil and rosuvastatin calcium in healthy Korean subjects
.

CONTEXT: A fixed-dose combination (FDC) of candesartan and rosuvastatin was recently developed for the treatment of cardiovascular disease and expected to enhance patient compliance. OBJECTIVE: This study was performed to compare the single-dose pharmacokinetic properties and tolerability of DP-R208 (candesartan and rosuvastatin FDC) to those of each component administered alone in healthy Korean male volunteers. MATERIALS AND METHODS: A total of 40 healthy Korean volunteers were enrolled in this randomized, open-label, single-dose, two-treatment, two-way crossover study. During each treatment period, subjects received the test formulation (FDC tablet containing candesartan and rosuvastatin) or reference formulation (co-administration of candesartan and rosuvastatin). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, and 48 hours post-dose. Safety and tolerability were assessed by the evaluation of adverse events (AEs), physical examinations, laboratory assessments, 12-lead electrocardiograms (ECGs), and vital sign measurements. RESULTS: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of Cmax, AUClast, and AUCinf were 0.86 - 1.00, 0.92 - 1.04, and 0.92 - 1.03 for candesartan, and 0.88 - 1.06, 0.91 - 1.08, and 0.91 - 1.03 for rosuvastatin, respectively. All of the AEs were mild, and there was no significant difference in the incidence of AEs between the formulations. Furthermore, the pharmacokinetic properties of the test and reference formulations met the regulatory criteria for bioequivalence. Discussion and conclusion: Both formulations were safe and well tolerated, and no significant difference was observed in the safety assessments of the treatments.
.

Comparative pharmacokinetic and tolerability evaluation of two simvastatin 20 mg formulations in healthy Korean male volunteers.

Simvastatin is used to reduce plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is primarily used to treat hypercholesterolemia. This study was conducted to assess the bioequivalence between the generic formulation of simvastatin 20 mg and the branded formulation of simvastatin 20 mg. A generic formulation of simvastatin 20 mg tablet was developed and the pharmacokinetics of the generic formulation were compared with those of the branded formulation of simvastatin 20 mg tablet in 33 healthy male volunteers after a single oral dose in a randomized, open-label, two-period, two-sequence, crossover study. The reference (Zocor®, MSD Korea LTD.) and test (Simvarotin®, Korea Arlico Pharm Co., Ltd.) formulations, two 20 mg tablets each, were administered to all subjects in fasting status. The serial blood samples for pharmacokinetic analysis were collected before dosing and up to 24 hours post-dose, and plasma concentrations of simvastatin were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters including Tmax, Cmax, AUClast, AUCinf and t½ were calculated for both formulations by non-compartmental method, and the log-transformed Cmax and AUClast were compared statistically. Geometric mean ratios (90% confidence intervals) of the test to the reference formulation in Cmax and AUClast were 0.9652 (0.8302-1.1223) and 0.9891 (0.8541-1.1455), respectively. No significant differences in tolerability profiles were noted between the two formulations. The two formulations of simvastatin 20 mg tablets exhibited comparable pharmacokinetic profiles and 90% confidence intervals were within the acceptable range of bioequivalence criteria.