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1.

Purpose

The ability of sophisticated sensors and medical devices to monitor critical biomarkers has the potential to greatly advance precision medicine initiatives. A stakeholder event was organized to develop working models for the evolution of the field.

Methods

A workshop devoted to the subject matter was held at the Tufts Clinical and Translational Science Institute involving clinicians, device developers, regulators, engineers, and scientists.

Findings

Several areas for collaborative development were identified and interested teams offered resources for development of research programs.

Implications

The diversity of relevant stakeholders presents a major opportunity and challenge in translational research. It is evident that the CTSI national network can take a leadership role in the rapidly advancing and potentially transformative field of digital biomarkers.  相似文献   

2.

Purpose

The aim was to investigate the stability of cefazolin in elastomeric infusion devices.

Methods

Elastomeric devices (Infusor LV) that contain cefazolin (3 g/240 mL and 6 g/240 mL) were prepared and stored at 4°C for 72 hours and then at 35°C for 12 hours, followed by 25°C for 12 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentration of cefazolin. Samples were also assessed for changes in pH, solution color, and particle content.

Findings

Cefazolin retained acceptable chemical and physical stability over the studied storage period and conditions.

Implications

These findings will allow the administration of cefazolin by the Infusor LV elastomeric device in the outpatient and remote settings.  相似文献   

3.

Purpose

Understanding how sex impacts the efficacy of anticancer agents is a crucial step toward personalized and precision medicine. This review and meta-analysis evaluated sex differences in hazard ratios (HRs) of progression-free survival and overall survival in representative Phase III clinical trials of non–small-cell lung cancer (NSCLC).

Methods

Data were extracted from 24 large-scale clinical trials that included 12,000 male and 7000 female patients. The data were examined for HR differences between subgroups by sex, smoking status, and age, and for potential sex–smoking status, sex–age, and sex–drug interactions, during cancer treatment.

Findings

Summarized information revealed variations in the influences of sex, smoking status, and age on the efficacy of drugs used for the treatment of NSCLC. The male and female subgroups had different HR values. Smoking status, age, and the percentage of female patients in a treatment group had no influence on the sex HR. The sex difference was supported by a set of data collected from all journals.

Implications

The findings from this meta-analysis are important for assessing potential toxicity during drug treatment in both sexes. The outcomes measures of a drug in clinical application should be specified by subpopulation, such as males versus females, as a first step in personalized medicine.  相似文献   

4.

Purpose

This review provides an update on the investigations and treatment options for gastroparesis.

Methods

A comprehensive literature search of Medline, PubMed, Embase and OVID was conducted which included all systematic reviews and research articles that focused on the diagnosis, investigations and management diabetic gastroparesis.

Findings

Dietary modifications and pharmacologic treatment with prokinetics to increase gastric motility form the mainstay of treatment. However, the use of prokinetics is limited by adverse effects and serious adverse effects, leaving metoclopramide as the only drug approved by the US Food and Drug Administration for the treatment of gastroparesis. Newer therapies, including motilin receptor agonists, ghrelin receptor agonists, and neurokinin receptor antagonists, are currently being investigated. Transpyloric stenting, gastric electrical stimulation, and gastric per-oral endoscopic myotomy provide mechanical options for intervention, and surgical interventions in severe intractable gastroparesis include laparoscopic pyloroplasty or gastrectomy.

Implications

Advances to better understand the pathophysiology and management of diabetic gastroparesis have been limited, especially with discordance between symptoms and severity of delay in gastric emptying. Established treatment options are limited; however, recent pharmacologic and surgical interventions show promise.  相似文献   

5.

Purpose

The extent to which new drug developers can benefit financially from shorter development times has implications for development efficiency and innovation incentives. We provided a real-world example of such gains by using recent estimates of drug development costs and returns.

Methods

Time and fee data were obtained on 5 single-source manufacturing projects. Time and fees were modeled for these projects as if the drug substance and drug product processes had been contracted separately from 2 vendors. The multi-vendor model was taken as the base case, and financial impacts from single-source contracting were determined relative to the base case.

Findings

The mean and median after-tax financial benefits of shorter development times from single-source contracting were $44.7 million and $34.9 million, respectively (2016 dollars). The after-tax increases in sponsor fees from single-source contracting were small in comparison (mean and median of $0.65 million and $0.25 million).

Implications

For the data we examined, single-source contracting yielded substantial financial benefits over multi-source contracting, even after accounting for somewhat higher sponsor fees.  相似文献   

6.

Objective

To identify a correlation between family support and maternal self-efficacy of adolescent mothers.

Method

This cross-sectional study applied a consecutive sampling technique. The sample was 100 primiparous adolescent mothers. Instruments utilized were structured questionnaires, including a demographic questionnaire, Maternal Efficacy Questionnaire (MEQ), Postpartum Support System, Edinburgh Postnatal Depression Scale (EPDS), and Infant Characteristics Questionnaire (ICQ). The correlation of family support and maternal self-efficacy was analyzed using chi-square and logistic regression.

Results

The results showed a significant correlation between family support and maternal self-efficacy of adolescent mothers. The family support that most influenced maternal self-efficacy of adolescent mothers was family instrument support, with Wald value of 34.720.

Conclusions

Instrument support most affects maternal self-efficacy of adolescent mothers and encourages adolescents performing nurturing and mothering roles.  相似文献   

7.

Purpose

This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*.

Methods

In this randomized, blinded, single-dose comparative PK study, healthy male subjects were randomized to receive a single 6 mg/kg IV dose of HD201 or EU-trastuzumab. The primary PK end point was AUC0–∞. Equivalence was determined by using the predefined margins of 0.8 to 1.25. Other PK parameters were included as secondary end points.

Findings

Baseline demographic characteristics for the 73 randomized subjects were similar across the 2 groups: median age 29 and 30 years old (ranges 19 - 45), median weight 78.6 and 81.7 kg (ranges 60.2 – 101). The 90% CIs for the geometric least squares mean of the AUC0–∞ were included within the margins of 0.8 to 1.25. All other PK parameters were comparable for both HD201 and EU-trastuzumab. The proportions of subjects who experienced adverse events related to the study drug were 61.8% and 82.9% in the HD201 and EU-trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug were infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose.

Implications

This study reported the PK equivalence between HD201 and EU-trastuzumab. HD201 was well tolerated with no safety concerns after single-dose administration in healthy male subjects. EudraCT No.: 2012-000805-56.  相似文献   

8.

Purpose

The purpose of this study was to examine the efficacy and safety of adding ω-3 fatty acids to rosuvastatin in patients with residual hypertriglyceridemia despite statin treatment.

Methods

This study was a multicenter, randomized, double-blind, placebo-controlled study. After a 4-week run-in period of rosuvastatin treatment, the patients who had residual hypertriglyceridemia were randomized to receive rosuvastatin 20 mg/d plus ω-3 fatty acids 4 g/d (ROSUMEGA group) or rosuvastatin 20 mg/d (rosuvastatin group) with a 1:1 ratio and were prescribed each medication for 8 weeks.

Findings

A total of 201 patients were analyzed (mean [SD] age, 58.1 [10.7] years; 62.7% male). After 8 weeks of treatment, the percentage change from baseline in triglycerides (TGs) and non–HDL-C was significantly greater in the ROSUMEGA group than in the rosuvastatin group (TGs: ?26.3% vs ?11.4%, P < 0.001; non–HDL-C: ?10.7% vs ?2.2%, P = 0.001). In the linear regression analysis, the lipid-lowering effect of ω-3 fatty acids was greater when baseline TG or non?HDL-C levels were high and body mass index was low. The incidence of adverse events was not significantly different between the 2 groups.

Implications

In patients with residual hypertriglyceridemia despite statin treatment, a combination of ω-3 fatty acids and rosuvastatin produced a greater reduction of TGs and non?HDL-C than rosuvastatin alone. Further study is needed to determine whether the advantages of this lipid profile of ω-3 fatty acids actually leads to the prevention of cardiovascular event. ClinicalTrials.gov identifier: NCT03026933.  相似文献   

9.

Purpose

Acute myeloid leukemia (AML) disproportionately affects older adults; the prognosis in this subpopulation is generally poor, with variable use of inpatient chemotherapy. This study characterizes treatment patterns, hospitalizations, and outcomes among older patients with AML.

Methods

Using the Centers for Medicare & Medicaid Services' 2010–2012 100% Limited Data Set (LDS), data from all hospital claims from fee-for-service Medicare beneficiaries between 60 and 75 years of age with newly diagnosed AML and ≥1 hospitalization were analyzed.

Findings

Among 3700 identified patients with AML, 1979 (53.5%) received chemotherapy. Hospitalization rates were highest initially and then declined over time, irrespective of chemotherapy use. The mean length of initial hospital stay was longer in patients receiving chemotherapy. Intensive care unit admissions occurred in 33% of initial hospitalizations. Factors associated with receiving chemotherapy included younger age, fewer comorbidities, and the absence of prior hematologic disorders. Chemotherapy was associated with significantly increased survival compared with no chemotherapy (P < 0.0001).

Implications

AML in older patients is associated with frequent hospitalizations and intensive care unit admissions. New treatment options with more favorable risk-to-benefit profiles are needed in this population.  相似文献   

10.

Purpose

The goal of this study was to compile a review of topics pertinent to the use of immune checkpoint inhibitors in gynecologic malignancies, including foundation for use, current agents available and trials in gynecologic cancers, special populations of interest, identification and management of toxicities, and considerations in predictive biomarkers and response assessment.

Methods

A literature review of selected topics in reference to immune checkpoint inhibitors and gynecologic cancers was conducted on PubMed and the US Food and Drug Administration drug search application. A review of current and ongoing clinical trials was performed in clinicaltrials.gov, and selected preliminary results reported in PubMed abstracts and through the American Society of Clinical Oncologists were compiled.

Findings

Although immunotherapy in gynecologic malignancy is relatively new, 7 agents are currently approved for use in other oncologic indications, and a multitude of trials in gynecologic cancer are ongoing. Immunotherapy has a specific set of drug toxicities that manifest and are managed unlike traditional cytotoxic therapies.

Implications

Application of the knowledge of immune checkpoint inhibitor use in gynecologic cancers will improve care for women with cancers of the female reproductive tract. As more complex and newer immunotherapies evolve, it will be vital to accurately characterize each specific drug class and management thereof.  相似文献   

11.

Purpose

This study investigated whether participation in aerobic exercise enhances the effects of aphasia therapy, and the degree to which basal serum brain-derived neurotropic factor (BDNF) concentrations fluctuate after the beginning of aerobic exercise or stretching activities in individuals with poststroke aphasia.

Methods

The study used a single-subject, multiple-baseline design. Seven individuals with chronic poststroke aphasia participated in 2 Blocks of aphasia therapy: aphasia therapy alone (Block 1), followed by aphasia therapy with the addition of aerobic activity via bicycle ergometer (n = 5) or stretching (n = 2) (Block 2). Serum BDNF concentrations from blood draws were analyzed in 4 participants who exercised and in 1 participant who stretched.

Findings

Three of the five exercise participants demonstrated larger Tau-U effects when aphasia therapy was paired with aerobic exercise, whereas 1 of the 2 stretching participants demonstrated a larger effect size when aphasia therapy was paired with stretching. Group-level comparisons revealed a greater overall increase in effect size in the aerobic exercise group, as indicated by differences in Tau-U weighted means. BDNF data showed that all 4 exercise participants demonstrated a decrease in BDNF concentrations during the first 6 weeks of exercise and an increase in BDNF levels near or at baseline during the last 6 weeks of exercise. The stretching participant did not show the same pattern.

Implications

Additional research is needed to understand the mechanism of effect and to identify the factors that mediate response to exercise interventions, specifically the optimal dose of exercise and timing of language intervention with exercise. ClinicalTrials.gov identifier: NCT01113879.  相似文献   

12.

Purpose

Although vancomycin has been the mainstay of therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections, its effectiveness has been challenged. Combination therapy may be used for patients with persistent MRSA bacteremia refractory to initial therapy. Studies have reported in vitro synergy between vancomycin and ceftaroline; however, clinical experience with this therapy is limited. Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline.

Methods

Between January 2014 and August 2016, 5 patients were identified who received vancomycin and ceftaroline combination therapy due to persistent bacteremia or deterioration of their clinical status on vancomycin alone (despite a vancomycin MIC within the susceptible range).

Findings

Five patients presented with MRSA bacteremia secondary to endocarditis (n = 2), epidural abscess (n = 2), or left iliopsoas abscess (n = 1). Four of the 5 patients experienced microbiologic cure, and 1 patient transitioned to palliative care.

Implications

This case series serves to describe additional clinical experience with vancomycin and ceftaroline combination therapy. This combination may be considered when vancomycin monotherapy does not lead to microbiological and/or clinical improvement in patients with metastatic MRSA bacteremia. Additional studies are warranted to further define its role in salvage therapy for persistent MRSA bacteremia.  相似文献   

13.

Objective

To introduce the prenatal regenerative medicine service at Mayo Clinic for fetal endoscopic tracheal occlusion (FETO) care for severe congenital diaphragmatic hernia (CDH).

Patients and Methods

Two cases of prenatal management of severe CDH with FETO between January and August 2017 are reported. Per protocol, FETO was offered for life-threatening severe CDH at between 26 and 29 weeks' gestation. Regenerative outcome end point was fetal lung growth. Gestational age at procedure and maternal and perinatal outcomes were additional monitored parameters.

Results

Diagnosis by ultrasonography of severe CDH was based on extremely reduced lung size (observed-to-expected lung area to head circumference ratio [o/e-LHR], eg, o/e-LHR of 20.3% for fetus 1 and 23.0% for fetus 2) along with greater than one-third of the liver herniated into the chest in both fetuses. Both patients underwent successful FETO at 28 weeks. At the time of intervention, no maternal or fetal complications were observed. Postintervention, fetal lung growth was observed in both fetuses, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2. The balloons were removed successfully at 35 weeks and 4 days by ultrasound-guided puncture in the first patient and at 32 weeks and 3 days by ex utero intrapartum therapy-to-airway procedure in the second patient. Postnatal management followed standard of care with patch CDH therapy. At discharge, one patient was breathing normally, whereas the other required minimal nasal cannula oxygen support.

Conclusion

The successful launch of the first fetoscopic therapy for CDH at Mayo Clinic reveals its feasibility and safety, with early signs of benefit documented by fetal lung growth and reversal of severe pulmonary hypoplasia.

Trial Registration

clinicaltrials.gov Identifier: G170062.  相似文献   

14.

Purpose

As part of the approval process, regulatory authorities often require postauthorization studies that involve patient registries; it is unknown, however, whether such registry studies are adequately completed. We investigated whether registry studies for new drugs were performed as agreed at time of approval.

Methods

This study reviewed protocols and follow-up reports for 73 registry studies that were proposed for 43 drugs approved by the Committee for Medicinal Products for Human Use in Europe in the period 2007 to 2010.

Results

The data lock point of January 1, 2016, was taken to allow a 5-year follow-up period for each drug after approval. At that time, 2 studies (3%) in registries had been finalized, 19 registries (26%) had not enrolled any patients, and 52 studies (71%) were ongoing. The median enrollment was 31% (interquartile range [IQR], 6–104) of the required number of patients for 41 registry studies that had a predefined sample size, 30% (IQR, 2–101) for nonimposed registries, and 61% (IQR, 18–144) for imposed registries.

Implications

Enrollment of patients into postapproval registries is poor, although the results for imposed registries seem better. Currently, registries only have a limited impact on resolving gaps in the knowledge of a drug’s benefits and risks at time of marketing authorization.  相似文献   

15.

Purpose

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions.

Methods

A literature search of Medline and PubMed was conducted (January 2000–October 2017) to identify recent reports of targeted drugs in EOC.

Findings

A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection.

Implications

The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics.  相似文献   

16.

Purpose

Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation.

Methods

Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC0–t, Cmax, and Cmax/AUC0–t) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed.

Findings

Forty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m2). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events.

Implications

Bioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239.  相似文献   

17.

Purpose

Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3.

Methods

These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3.

Findings

Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants.

Implications

The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).  相似文献   

18.

Purpose

This study was designed to evaluate the safety and pharmacokinetic profiles of MRX-I tablet, an oxazolidinone antibacterial agent, in healthy Chinese subjects.

Methods

The study was composed of 3 sequential periods. Period 1 was a randomized, double-blind, placebo-controlled, sequential ascending dose (50 to 1800 mg) study. Period 2 included one arm as a randomized, open-label, 3-period, 3 × 3 Latin square single-dose study of 300, 600, and 900 mg MRX-I administration and another arm as a crossover study to evaluate high-fat diet effect. Period 3 was a randomized, double-blind, placebo-controlled multiple-dose study with 600 or 800 mg, q12h regimens over 15 days.

Findings

MRX-I was rapidly absorbed and reached peak plasma concentration at about 2 hours post dose. The Cmax was 8.07, 12.24, and 15.25 mg/L and the corresponding AUC0?∞ 29.21, 48.27, and 59.60 mg/h/L, in 300-, 600-, and 900-mg dosing groups, respectively. High-fat diet increased the exposure of MRX-I. No discernable drug accumulation was observed after 15 days of continuous drug administration. About 2% of MRX-I was excreted via kidneys in unchanged form. No obvious hematologic toxicity by MRX-I was observed during the entire study. Based on Monte Carlo simulation, 600 or 800 mg BID can produce satisfactory efficacy against methicillin-resistant Staphylococcus aureus.

Implications

MRX-I was well tolerated in healthy Chinese subjects (50–1800 mg). No serious or severe adverse effects were observed. MRX-I 600 or 800 mg BID up to 15 days can be recommended in future clinical trials. Chinese Clinical Trial Registration (http://www.chinadrugtrials.org.cn) identifier: CTR20131214.  相似文献   

19.

Purpose

Diabetic peripheral neuropathy (DPN) is the commonest cause of neuropathy worldwide, and its prevalence increases with the duration of diabetes. It affects approximately half of patients with diabetes. DPN is symmetric and predominantly sensory, starting distally and gradually spreading proximally in a glove-and-stocking distribution. It causes substantial morbidity and is associated with increased mortality. The unrelenting nature of pain in this condition can negatively affect a patient's sleep, mood, and functionality and result in a poor quality of life. The purpose of this review was to critically review the current literature on the diagnosis and treatment of DPN, with a focus on the treatment of neuropathic pain in DPN.

Methods

A comprehensive literature review was undertaken, incorporating article searches in electronic databases (EMBASE, PubMed, OVID) and reference lists of relevant articles with the authors' expertise in DPN. This review considers seminal and novel research in epidemiology; diagnosis, especially in relation to novel surrogate end points; and the treatment of neuropathic pain in DPN. We also consider potential new pharmacotherapies for painful DPN.

Findings

DPN is often misdiagnosed and inadequately treated. Other than improving glycemic control, there is no licensed pathogenetic treatment for diabetic neuropathy. Management of painful DPN remains challenging due to difficulties in personalizing therapy and ascertaining the best dosing strategy, choice of initial pharmacotherapy, consideration of combination therapy, and deciding on defining treatment for poor analgesic responders. Duloxetine and pregabalin remain first-line therapy for neuropathic pain in DPN in all 5 of the major published guidelines by the American Association of Clinical Endocrinologists, American Academy of Neurology, European Federation of Neurological Societies, National Institute of Clinical Excellence (United Kingdom), and the American Diabetes Association, and their use has been approved by the US Food and Drug Administration.

Implications

Clinical recognition of DPN is imperative for allowing timely symptom management to reduce the morbidity associated with this condition.  相似文献   

20.

Purpose

Nemonoxacin, a nonfluorinated quinolone, has been approved in Taiwan and mainland China for the treatment of bacterial infection. Whether nemonoxacin is associated with the adverse events of other quinolones, such as the risk for QT-interval prolongation, which has led to the withdrawal of several fluoroquinolones from the market, needs to be elucidated.

Methods

The effects of nemonoxacin on thorough QT/QTc interval was investigated in this randomized, placebo- and positive-controlled crossover study conducted according to the International Conference on Harmonisation E14 guideline. Forty-eight healthy adults received a single oral dose of nemonoxacin 500 mg (therapeutic dose), nemonoxacin 750 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 cohorts (Williams Latin square design) in the fasted condition. After a 7-day washout, 6 male and 6 female subjects were orally administered a 500-mg dose of nemonoxacin after high-fat food intake. The primary end point was the change in QT interval corrected for heart rate using the Fridericia formula (QTcF). The secondary end point was the change in QT interval corrected for heart rate using the Bazett formula (QTcB).

Findings

The study revealed that nemonoxacin was classified as not likely dangerous at the therapeutic dose (500 mg) and as potentially dangerous at the supratherapeutic dose (750 mg). The Tmax of nemonoxacin was 1 to 2 hours after administration, and the elimination half-life was 5 to 7 hours, in the fasted conditions. High-fat food intake had significant effects on the Tmax, Cmax, AUC0–∞, and QT/QTc interval of nemonoxacin compared with these values in the fasted condition. A correlation between QTcF and the plasma drug concentration of nemonoxacin was not observed.

Implications

Nemonoxacin at the clinically therapeutic and supratherapeutic doses had a prolongation effect on QT/QTc. ClinicalTrials.gov identifier: NCT03362853.  相似文献   

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