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1.
Vikas K. Dawra Vaishali Sahasrabudhe Yali Liang Kyle Matschke Haihong Shi Anne Hickman Didier Saur Steven G. Terra David L. Cutler 《Clinical therapeutics》2018,40(9):1538-1547
Purpose
Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin.Methods
Twelve healthy adult subjects were enrolled in this open-label, 2-period, fixed-sequence study and received ertugliflozin 15mg on day 1 of period 1, followed by rifampin 600mg once daily on days 1 to 10 in period 2. On day 8 of period 2, ertugliflozin 15mg was coadministered with rifampin 600mg. Plasma samples for ertugliflozin pharmacokinetic analysis were collected during 72hours after dosing on day 1 of period 1 and day 8 of period 2 and analyzed using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis of concentration-time data. Natural log transformed AUC0–∞ and Cmax of ertugliflozin were analyzed using a mixed-effects model with treatment as a fixed effect and subject as a random effect.Findings
After administration of ertugliflozin 15mg alone or with rifampin, the Tmax was 1hour. The mean t½ was 12.3hours for ertugliflozin alone and 9.2hours with steady-state rifampin. Geometric mean ratios for AUC0–∞ and Cmax were 61.2% (90% CI, 57.2%–65.4%) and 84.6% (90% CI, 74.2%–96.5%), respectively. Ertugliflozin was well tolerated when administered alone or with rifampin.Implications
Coadministration of ertugliflozin with rifampin decreased ertugliflozin AUC0–∞ and Cmax by 39% and 15%, respectively. The effect of the reduced exposure was evaluated using the ertugliflozin dose-response model. The model predicted that a 5-mg ertugliflozin dose after coadministration with rifampin is expected to maintain clinically meaningful glycemic efficacy. Therefore, no dose adjustment of ertugliflozin is recommended when ertugliflozin is coadministered with a UGT and CYP inducer, such as rifampin. 相似文献2.
Hailan Wu Shengxin Xie Jicheng Yu Yuancheng Chen Jufang Wu Beining Guo Zhenghai Zhu Ying Zhou Zhiqiang Wang Jing Zhang 《Clinical therapeutics》2018,40(9):1548-1555
Purpose
The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.Methods
A single-center, open, multidose trial was conducted in 16 patients with intra-abdominal anaerobic infection. Patients received levornidazole at 500mg q12h by intravenous infusion for 3 to 7days. The plasma samples collected before and after the last dose were analyzed by the LC-MS/MS method to determine the concentration of levornidazole. The PK parameters of levornidazole were calculated, and the PK profiles of levornidazole after the dosing regimen of 750mg q24h for 7days were simulated based on the linear PK profile of levornidazole. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment (PTA) of both dosing regimens at steady-state against Bacteroides fragilis.Findings
After administration of the last dose of 500mg of levornidazole, the mean (SD) Cmax_ss, AUC0-12, and t1/2 of levornidazole were 24.0 (5.37) μg/mL, 176.59 (29.22) μg·h/mL, and 11.03 (1.34) hours, respectively. The mean (SD) CLss and Vss of levornidazole were 2.90 (0.47) L/h and 45.90 (7.44) L, respectively. The mean (SD) distribution volume of central compartment (V1) and distribution volume of peripheral compartment (V2) were 26.71 (8.51) L and 19.21 (10.86) L, respectively. On the basis of simulation, the accumulation ratio of levornidazole in the 750mg q24h dosing regimen was 30.2% lower than the value in the 500mg q12h dosing regimen. Forthe 2 dosing regimens, the Cmax_ss, AUC0–τ, AUC0–∞, CLss, and Vss did not produce a significant difference between patients and healthy volunteers (P > 0.05). The cumulative fraction of response of levornidazole against B fragilis was >90%, and the probability of target attainment after both dosing regimens was >90%, when the MIC was ≤1 μg/mL.Implications
No significant differences were found in the PK profiles of levornidazole at steady state between the patients with intra-abdominal anaerobic infection and healthy volunteers. The clinical conventional 750mg q24h regimen can achieve similar clinical and microbiological efficacies against anaerobic in the patients after the 500mg q12h regimen. 相似文献3.
Yong Kyun Kim Dong-Hwan Lee Jaehyun Jeon Hang-Jea Jang Hyeon-Kuk Kim Kyubok Jin Sung-Nam Lim Sung Sook Lee Bong Soo Park Yang Wook Kim Jae-Gook Shin Sungmin Kiem 《Clinical therapeutics》2018,40(8):1384-1395
Purpose
The aim of this study was to investigate the population pharmacokinetic (PK) profile of meropenem in Korean patients with acute infections.Methods
The study included 37 patients with a creatinine clearance ≤50 or >50 mL/min who received a 500- or 1000-mg dose of meropenem, respectively, infused intravenously over 1 hour every 8 hours. Blood samples were collected before and at 1, 1.5, and 5 hours after the start of the fourth infusion. The population PK analysis was conducted by using nonlinear mixed effect modeling software (NONMEM). Monte-Carlo simulations were performed to identify optimal dosing regimens.Findings
Thirty-seven subjects completed the study. Meropenem PK variables were well described by using a one-compartment model. The typical values (relative SE) for weight-normalized clearance (CL) and Vd were 0.266 L/h/kg (12.29%) and 0.489 L/kg (11.01%), respectively. Meropenem CL was significantly influenced by the serum creatinine level, which explained 11% of the interindividual CK variability. The proposed equation to estimate meropenem CL in Korean patients was as follows: CL (L/h)?=?0.266?×?weight?×?[serum creatinine/0.74]–1.017. The simulation results indicate that the current meropenem dosing regimen may be suboptimal in patients infected with normal or augmented renal function.Implications
Prolonged infusions of meropenem over at least 2 hours should be considered, especially in patients with augmented renal function and those infected with pathogens for which the minimum inhibitory meropenem concentration is >1 μg/mL. Our results suggest an individualized meropenem dosing regimen for patients with abnormal renal function and those infected with pathogens with decreased in vitro susceptibility. 相似文献4.
Yun Liu Brian Tomlinson Jiyuan Guo Mahnaz Asgharnejad Lars Bauer Erwin Surmann Xiaojuan Guo Jan-Peer Elshoff 《Clinical therapeutics》2018,40(7):1108-1121.e8
Purpose
The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of rotigotine in healthy Chinese men.Methods
In treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2–6); treatment period 2 (days 6–14) involved multiple doses of rotigotine 2 mg/24 hours (days 7–9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10–12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring.Results
Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ～8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0–24,ss values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0–24,ss of both unconjugated and total rotigotine were ～2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature–stable formulation of rotigotine were highly comparable to the cold-chain formulation.Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures.Implications
PK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature–stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796. 相似文献5.
Purpose
The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients.Methods
A literature search of PK studies was performed by using MEDLINE (1946–December 2017) and EMBASE (1910–December 2017); we identified further studies by citation tracking (Web of Science) and checked references of retrieved studies and review articles. All studies were included that were published in English, Chinese, or German; conducted in critically ill adult patients receiving lorazepam, midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, remifentanil, morphine, or fentanyl infusion for ≥24 hours; and reported PK parameters. When appropriate, we conducted a meta-analysis on volume of distribution at steady state (Vdss) (liters), clearance (Cl) (liters per hour), and elimination t1/2 (hours) by using a DerSimonian-Laird random effects model to estimate the summary mean and 95% CIs. Results were compared with commonly reported PK ranges in 70-kg noncritically ill patients.Findings
Thirty-three randomized controlled trials and prospective cohort studies were identified involving 1803 adult critically ill patients with 35 drug treatment arms: fifteen midazolam (n?=?906) studies, three dexmedetomidine (n?=?561), nine propofol (n?=?165), four lorazepam (n?=?86), one morphine (n?=?20), two remifentanil (n?=?55), and one sufentanil (n?=?10). Each study showed large variations in Vdss, Cl, and elimination t1/2 within and between individual participants. High clinical and methodical heterogeneity between the dexmedetomidine studies prevented the direct comparison of PK parameters between critically ill and noncritically ill patients. Use of midazolam, propofol, and lorazepam in critically ill patients was associated with at least a 2- to 4-fold increase in Vdss compared with noncritically ill patients; Cl decreased ～2-fold for midazolam and 10-fold for morphine. Critically ill patients receiving prolonged infusions of midazolam, propofol, remifentanil, and sufentanil had at least 2-fold longer elimination or terminal t1/2 than noncritically ill patients.Implications
These findings show a marked difference in many PK parameters from those reported for noncritically ill patients. Initiatives to improve the delivery of prolonged sedatives and analgesic infusions should be informed by PK parameters (Vdss, context-sensitive t1/2, and elimination t1/2) and data derived from critically ill patients. 相似文献6.
Robert Wilson Emily Jarvis Mickael Montembault J. Nicole Hamblin Edith M. Hessel Anthony Cahn 《Clinical therapeutics》2018,40(8):1410-1417
Purpose
Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.Methods
This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n?=?12) and B (n?=?12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n?=?6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days.Findings
21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0–24 values were 174.3 pg/mL (96.9–313.3) and 694.6 pg·h/mL (503.5–958.2) for 100 μg and 398.9 pg/mL (318.3–500.1) and 1699.6 pg·h/mL (1273.3–2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ～2- to 4-fold higher than on the single dose (peak, trough, and AUC0–24 levels), achieving steady-state by day 6. Mean AUC0–24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non–drug-related adverse events were observed; neither was serious or resulted in withdrawal.Implications
Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ～23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325. 相似文献7.
Su-jin Rhee Howard Lee Li Young Ahn Kyoung Soo Lim Kyung-Sang Yu 《Clinical therapeutics》2018,40(10):1720-1728.e2
Purpose
Pregabalin and thioctic acid are likely to be used concomitantly for the treatment of painful diabetic neuropathy. In this study, the pharmacokinetic interaction between pregabalin and thioctic acid was investigated at steady state.Methods
A randomized, open-label, 6-sequence, 3-period, 3-treatment crossover study was conducted in 42 healthy male volunteers. The volunteers randomly received pregabalin 300 mg BID for 6 times, thioctic acid 600 mg once daily for 3 times, or the combination of pregabalin and thioctic acid. Serial blood samples were collected up to 24 hours after the last dosing in each period. Pharmacokinetic parameters were calculated by using noncompartmental analysis methods.Findings
The mean concentration–time curves were similar between each drug alone and in combination with the other drug. The 90% CIs of the geometric mean ratios with and without the co-administered drug for Cmax at steady state and AUC during the dosing interval were well within the conventional bioequivalence range of 0.8 to 1.25, except for Cmax at steady state for thioctic acid, which barely exceeded only the lower bound (0.78–1.15). Co-administered pregabalin and thioctic acid was well tolerated.Implications
Repeatedly administered pregabalin and thioctic acid do not interact pharmacokinetically. This study suggests that the combination of pregabalin and thioctic acid can safely be administered concomitantly without dose adjustment. ClinicalTrials.gov identifier: NCT01808300. 相似文献8.
Cheng-zi Zuo Yi Gong Xiang-yu Hou Yi-fan Zhang Wen-xing Peng Rong-hua Zhu Da-fang Zhong Xiao-yan Chen 《Clinical therapeutics》2018,40(8):1347-1356
Purpose
Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters.Methods
In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4′-hydroxymethyl metabolite [M1] and 4′-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study.Findings
All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0–t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0–t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments.Implications
Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib?+?fluconazole/imrecoxib) for AUC0–t was 1.72 (90% CI, 1.41–2.11) and for Cmax it was 1.88 (90% CI, 1.59–2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors. 相似文献9.
Background
Advanced Practice Registered Nurses (APRNs) provide access to cost-effective, high quality care. APRNs are underutilized in states that restrict their practice. Removing restrictions could expand access to quality health care, cost-effectively relieve the physician shortage, and contribute economically.Purpose
This study forecasts the health system and economic impacts of reducing practice restrictions for Florida APRNs.Methods
The analysis utilized a number of data sources and IMPLAN software and estimated changes in APRN supply given less restrictive practice laws, and consequential health system and economic benefits.Findings
Between 2013 and 2025 APRN full time equivalents could increase an additional 11% with less restrictive practice regulations. This could eliminate or reduce the shortage of different types of physicians. Health care cost-savings could be $50 to $493 per resident. There would be a number of general economic benefits.Discussion
A number of health system and economic benefits would ensue from less restrictive APRN regulation. 相似文献10.
Purpose
Morphine ARER is a novel oral, abuse-deterrent, extended-release (ER) formulation of morphine sulfate with physical and chemical properties that deter misuse and abuse by nonoral routes of administration. Here we evaluate the relative bioavailability of morphine ARER and extended-release morphine.Methods
This single-dose, 2-treatment, 2-period, 2-sequence, randomized crossover study in healthy adult subjects compared the relative bioavailability of morphine ARER 100 mg to that of ER morphine 100 mg in the fasted condition. At 12 and 1.5 hours before dosing and 12 hours after dosing, all subjects received a 50-mg oral naltrexone tablet to minimize opioid-related side effects. Pharmacokinetic parameters including the AUC0–t, AUC0–∞, and Cmax of morphine and its metabolite morphine-6-glucuronide (M6G) were determined at various times up to 48 hours postdose. The bioequivalence of morphine ARER and ER morphine was determined using an ANOVA of the least-squares mean values of morphine and M6G bioavailability.Findings
Forty-nine subjects completed the study. Both morphine ARER and ER morphine exhibited peak plasma morphine and M6G concentrations of ～30 ng/mL and ～200 ng/mL, respectively, at 3 hours postdose. The 90% CIs of the ln-transformed values of morphine AUC0–t, AUC0–∞, and Cmax were within the 80% to 125% range for bioequivalence. M6G values also indicated bioequivalence of morphine ARER and ER morphine. The most common adverse events were nausea and somnolence.Implications
These data show that, in these subjects, morphine ARER was bioequivalent to ER morphine, a treatment for pain with well-established efficacy and safety profiles. 相似文献11.
Ignacio Conde-Carmona Sandra García-Medina Juan M. Jiménez-Vargas Alberto Martínez-Muñoz Sung-Hack Lee 《Clinical therapeutics》2018,40(10):1729-1740
Purpose
The aim of this study was to assess the pharmacokinetic interactions between a newly developed dipeptidyl peptidase (DPP)-4 inhibitor, gemigliptin, and metformin in healthy Mexican male volunteers, and the differences in the pharmacokinetic profile of gemigliptin between Korean and Mexican healthy volunteers.Methods
This was a multiple-dose, randomized, open-label, 3-way, 3-period crossover study. Subjects were randomized to 1 of 3 treatment sequences and received gemigliptin 50mg once a day, metformin1000mg BID, or both drugs during a 7-day treatment period, and underwent sampling for pharmacokinetic analysis and tolerability assessments. Point estimates and 90% CIs of Cmax,ss and AUCτ,ss least squares mean (LSM) ratios of the concurrent administration of gemigliptin?+?metformin to the administration of monotherapy with either drug were obtained, and the pharmacokinetic profile of gemigliptin observed was compared with that in healthy Korean volunteers studied during the initial development of gemigliptin.Findings
The coadministration of gemigliptin?+?metformin did not affect the pharmacokinetic characteristics of gemigliptin (LSM ratio [90% CI] for Cmax,ss and AUCτ,ss: 0.98 [0.87–1.10] and 0.94 [0.91–0.98], respectively) or metformin (LSM ratio [90% CI] for Cmax,ss and AUCτ,ss: 0.97 [0.88–1.08] and 1.02 [0.93–1.12], respectively) when administered as monotherapy and was well tolerated. In contrast with Korean healthy volunteers, Mexican subjects showed a modestly higher gemigliptin exposure (LSM ratio [90% CI] for AUCτ,ss: 1.22 [1.14–1.31]).Implications
The results of this study support, in ethnically different populations, the absence of drug–drug interactions between gemigliptin and metformin previously shown in Korean healthy volunteers. Considering the flat effect–concentration curve and wide therapeutic range of gemigliptin, the pharmacokinetic profile of gemigliptin observed in healthy Mexican and Korean subjects suggests that gemigliptin use in Mexican patients may be associated with outcomes, in terms of efficacy and tolerability, similar to those observed in the Korean population. ClinicalTrials.gov identifier: NCT03310749. 相似文献12.
Kwadwo A. Yeboah Amy Allspaw Akram Al-Makki Brian M. Shepler 《Clinical therapeutics》2018,40(9):1592-1595
Purpose
Several antihypertensive medications have been associated with various forms of sexual dysfunction. We present a case report of a premenopausal patient with hydralazine-associated amenorrhea.Methods
The Naranjo adverse drug reaction probability scale was used to assess causality. We also performed a literature search on PubMed to find publications that report hydralazine-associated amenorrhea.Results
The Naranjo scale generated a score of 6, suggesting a probable relationship between amenorrhea and hydralazine therapy. No publications associating hydralazine with amenorrhea were identified.Implications
A probable relationship exists between hydralazine and the development of amenorrhea. 相似文献13.
Xiaojiao Li Hong Chen Junqi Niu Guiling Chen Gong Shen Benedetta Massetto Diana M. Brainard Xiaoxue Zhu Hong Zhang Yanhua Ding 《Clinical therapeutics》2018,40(9):1556-1566
Purpose
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetic profile of sofosbuvir and its metabolites after a single dose of sofosbuvir 400mg and once daily dosing of sofosbuvir 400mg for 7days in healthy Chinese subjects.Methods
This Phase I, open-label, single- and multiple-dose study enrolled 14 Chinese subjects aged 18 to 45years with an approximately even distribution of healthy male (n?=?9) and nonpregnant, nonlactating female subjects (n?=?5). Subjects received a single oral dose of sofosbuvir 400mg (one tablet) (morning, fasted conditions; single-dose treatment). After a 3-day washout, subjects received oral sofosbuvir 400mg (one tablet) (morning, fasted) for 7days (multiple dose treatment).Findings
No significant accumulation of sofosbuvir, GS-566500, or GS-331007 was observed. Steady state of the major metabolite GS-331007 was achieved after 4days of consecutive dosing with sofosbuvir 400mg once daily. Sofosbuvir was generally well tolerated.Implications
Overall, this study supports the further evaluation of sofosbuvir 400mg in the Chinese population. The pharmacokinetic properties of sofosbuvir, GS-556500, and GS-311007 were found to be broadly similar in healthy Chinese subjects compared with non-Chinese subjects in previous sofosbuvir studies. ChinaDrugTrials.org.cn identifier: CTR20150249. 相似文献14.
Kristina S. Boye Reema Mody Jianmin Wu Maureen J. Lage Fady T. Botros Brad Woodward 《Clinical therapeutics》2018,40(8):1396-1407
Purpose
The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA1c) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment.Methods
The study used data from the Practice Fusion electronic health records database from October 2013 through June 2017. Adults with type 2 diabetes who initiated dulaglutide or insulin glargine therapy and had multiple recorded serum creatinine and/or HbA1c laboratory test results were included in the study. The dulaglutide cohort (n?=?1222) was matched to the insulin glargine cohort (n?=?13,869) using Mahalanobis distance matching with propensity score calipers. Multivariable analyses of the matched cohorts of individuals with serum creatinine results (n?=?1183 dulaglutide and 1183 insulin glargine) examined the association between intent-to-treat therapy and changes in eGFR. In addition, multivariable analyses were also conducted on a subset of these patients who also had recorded HbA1c tests (n?=?1088 dulaglutide and 1088 insulin glargine) to examine the association between changes in HbA1c during the 1 year postperiod.Findings
Among patients who initiated dulaglutide therapy, only 0.9% of patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 0.1% had an index eGFR <15 mL/min/1.73 m2. In contrast, 4.1% of insulin glargine–treated patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 1.2% had an index eGFR <15 mL/min/1.73 m2. Compared with patients who initiated therapy with insulin glargine, initiation of dulaglutide therapy was associated with a significantly smaller decrease in eGFR (?0.4 vs ?0.9 mL/min/1.73 m2; P?=?0.0024), a significantly smaller likelihood of having a 30% or greater reduction in eGFR (3.3% vs 4.1%; P < 0.0001), and a significantly larger reduction in HbA1c (?0.5% vs ?0.2%; P < 0.0001).Implications
In clinical practice, the use of dulaglutide was relatively more limited in patients with a higher degree of renal impairment compared with use of insulin glargine. However, initiation of dulaglutide therapy, compared with insulin glargine therapy, was associated with a significantly smaller decrease in eGFR and a larger reduction in HbA1c during the 1 year postperiod. 相似文献15.
Purpose
Respiratory syncytial virus (RSV) and influenza are important viral pathogens worldwide. Children, in particular, bear considerable burdens of morbidity and mortality associated with these viruses. There are limited therapeutic options for children infected with RSV or influenza. This review focuses on therapeutics for RSV and influenza that are currently under clinical investigation.Methods
This study used a systematic approach to identify prospective therapeutics in clinical trials and briefly reviewed those that are currently available for use in adults and children.Findings
Overall, we found 14 investigational drugs currently in clinical trials for RSV and 20 investigation drugs currently in clinical trials for influenza. These candidates range in development from Phase I to Phase III clinical trials.Implications
Both RSV and influenza are targets for active therapeutic research, and promising candidates for both viruses are currently in clinical development. 相似文献16.
Purpose
The objective of this review was to summarize the recent literature describing the current burden of disease due to herpesviruses in the antiviral and transplant era; describe mechanisms of action of antiviral agents and the development of resistance; summarize the literature of recent antiviral agents brought to market as well as agents under development; and to present literature on future strategies for herpesvirus therapeutics.Methods
An extensive search of the medical literature related to antiherpesviral therapy was conducted to compose this narrative review. Literature searches were performed via PubMed and ultimately 137 articles were included as most relevant to the scope of this article.Findings
Herpesviruses are a family of DNA viruses that are ubiquitous throughout human populations and share the feature of establishing lifelong infections in a latent phase with the potential of periodic reactivation. With the exception of herpes simplex virus, varicella zoster virus, and Epstein-Barr virus, which have a significant disease burden in individuals with normal immune function, the morbidity and mortality of the remaining viruses are primarily associated with the immunocompromised host. Over the last half-century, several agents have been tested in large randomized, placebo-controlled trials that have resulted in safe and effective antiviral agents for the treatment of many of these infections.Implications
With increasing use of antiherpesviral agents for extended periods, particularly in immunocompromised hosts, the emergence of resistant viruses has necessitated the development of newer agents with novel targets and better side-effect profiles. 相似文献17.
Manabu Kato Hitoshi Ishizuka Takashi Taguchi Kazuhito Shiosakai Emi Kamiyama Michio Sata Takafumi Yoshida 《Advances in therapy》2018,35(8):1239-1250
Introduction
The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a.Methods
This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety.Results
The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration–time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (Cmax) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to Cmax were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups.Conclusion
DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD.Trial registration
Japic CTI-No. 163135.Funding
Daiichi Sankyo Co. Ltd., Tokyo, Japan.18.
Purpose
Hepatitis C, a chronic disease with deadly consequences, is no longer predominantly a disease of older people.Methods
A limited search was conducted of the relevant literature on 2 topics: (1) the impact of hepatitis C on infants exposed by vertical transmission; and (2) the impact of hepatitis C infection on infected children and adolescents. The findings were supplemented by the first-hand experience of the authors.Findings
Young people, including women of childbearing age, infants, children, and adolescents, are being especially affected by hepatitis C infection secondary to the intravenous drug use and opioid epidemic. Unfortunately, estimates of disease in young populations are all misleading because universal screening has not been implemented.Implications
Lack of implementation of policies for screening and therapy on most affected populations will be responsible for perpetuation of this infection. In the era of highly effective therapy and a regimen that is approved by the US Food and Drug Administration for children, this outcome is unacceptable. 相似文献19.
Background
Pragmatic dissemination and implementation (D&I) research approaches can benefit patient care because they emphasize real-world settings and populations. Nurse scientists have an opportunity to reduce the gap between science and practice by using pragmatic D&I research and sustainability strategies.Purpose
This article discusses pragmatic models, methods, and measures used in D&I research and their relevance for nursing research and enhancing population health.Methods
Summary of pragmatic D&I models and related methods for designing a pragmatic studies. We discuss the RE-AIM framework and the PRECIS-2 planning aid and figure in detail. A case study is provided and application to nursing research is discussed.Discussion
Successful translation of pragmatic D&I research demands an approach that addresses external validity, and customization at multiple levels including the patient, clinician, and setting. Context is critically important, and it is never too early to design for dissemination.Conclusions
Pragmatic D&I approaches are needed to speed research translation, reduce avoidable waste of funding, improve clinical care, and enhance population health. Pragmatic D&I research is an area of tremendous opportunity for the nursing science community. 相似文献20.
Tomohiro Kusawake Donna Kowalski Akitsugu Takada Kota Kato Masataka Katashima James J. Keirns Michaelene Lewand Kenneth C. Lasseter Thomas C. Marbury Richard A. Preston 《Advances in therapy》2017,34(12):2612-2624