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1.
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2.
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3.
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4.
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5.
Bai-Li Song Meng Wan Dan Tang Chao Sun Yu-Bing Zhu Nyame Linda Hong-Wei Fan Jian-Jun Zou 《Clinical therapeutics》2018,40(7):1170-1178
Purpose
Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population.Methods
Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n?=?8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n?=?10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n?=?2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry.Findings
There were no significant differences in Cmax and AUC0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P?=?0.003] and 19.55 [2.19] ng/mL [P?=?0.004], respectively). The mean CAM AUC0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [P?=?0.007] and 27.08 [2.72] ng · h/mL [P?=?0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P?=?0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01).Implication
In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382. 相似文献6.
Vaishali Sahasrabudhe Steven G. Terra Anne Hickman Didier Saur Sangeeta Raje Haihong Shi Kyle Matschke Susan Zhou David L. Cutler 《Clinical therapeutics》2018,40(10):1701-1710
Purpose
Ertugliflozin, an oral, highly selective inhibitor of the sodium-glucose cotransporter 2, is approved in the United States and the European Union for the treatment of adults with type 2 diabetes mellitus. Hepatic impairment may affect, to varying degrees, the absorption, metabolism, and excretion of drugs and may be associated with a lower plasma protein binding compared with that in healthy individuals. This study was conducted to assess the effect of hepatic impairment on the pharmacokinetic (PK), safety, and tolerability profiles of ertugliflozin after administration of a single, 15-mg oral dose.Methods
This was a Phase I, open-label, single-dose study in healthy individuals (n?=?8) and those with moderate hepatic impairment (n?=?8). Eligible participants were men or women aged 18 to 75years with a body mass index of 18.0 to 40.5 kg/m2. Healthy individuals had normal hepatic function; patients with hepatic impairment had a Child-Pugh score of 7 to 9 points (moderate hepatic impairment). Blood samples were collected before dosing and during 96hours after dosing for evaluation of PK parameters. Adverse events were monitored throughout the study.Findings
The adjusted least squares geometric meanratios for total ertugliflozin AUC0–∞ and Cmax inpatients with moderate hepatic impairment comparedwith healthy individuals were 87.4% (90% CI, 68.1%–112.2%) and 78.7% (90% CI, 65.7%–94.2%), respectively. The AUC0–∞ and Cmax for unbound ertugliflozin were also similar between patients with moderate hepatic impairment and healthy individuals. Mean half-life estimates for ertugliflozin were similar (14.6vs 13.8 hours) in patients with moderate hepatic impairment and healthy individuals. The number of participants with all-causality treatment-emergent adverse events was similar for both groups (2 of 8 patients with moderate hepatic impairment and 3 of 8 healthy individuals).Implications
Moderate hepatic impairment had no clinically relevant effect on the PK and safety profiles of ertugliflozin. The results of this study support a recommendation for no dose adjustment of ertugliflozin in patients with mild or moderate hepatic impairment. Ertugliflozin was well tolerated when administered tohealthy individuals and patients with moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02115347. 相似文献7.
Jiaqing Wang Xia Chen Baoshi Yuan Weicong Wang Chunmin Xu Weiwei Zhao Pengpeng Zhao Yilong Wang Xingquan Zhao Yongjun Wang 《Clinical therapeutics》2018,40(10):1683-1691
Purpose
Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices–compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development.Methods
This 2-way crossover study was conducted in 10 healthy male volunteers. Eligible subjects were randomized, in a 1:1 ratio, to 1 of 2 dosing sequences: (1) SL edaravone 30mg, followed by edaravone 30mg IV infusion given over 30 minutes; or (2) edaravone 30mg IV infusion given over 30 minutes, followed by SL edaravone 30mg. The washout period between the 2 dosing periods was at least 24hours. Serial blood samples were collected in each dosing period. The bioavailability of the SL tablet was assessed using bioavailability analysis. Tolerability was evaluated throughout the study.Findings
The plasma concentration–time profile of the SL tablet was similar to that with the IV infusion. Amean (SD) Cmax of 2030.2 (517.2) ng/mL was reached within a median Tmax of 0.875hour, which was statistically significantly longer than the median Tmax with IV administration (0.5 hour). The Cmax with SL administration corresponded to 83.92% (90% CI, 73.22%–96.18%) of the Cmax with the start of IV infusion (2354.0 [336.6] ng/mL). The mean AUC0–t with SL dosing was 5420.07 (1429.75) h · ng/mL, which corresponded to 91.94% (90% CI, 86.81%–97.39%) of the AUC0–t with IV administration (5824.42 [1338.48] h · ng/mL). Two cases of adverse events were reported during the study; both were considered by the investigator to have been possibly not related to the study treatment.Implications
The bioavailability of the SL tablet of edaravone was 91.94%. Compared with IV administration, Cmax with SL administration was ～17% lower and Tmax was statistically significantly longer. The exposure differences can be addressed by modifying the strength of the SL tablet, and then conducting a second study to demonstrate the pharmacokinetic bioavailability of the sublingually administered new strength versus IV infusion of edaravone. 相似文献8.
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9.
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10.
Purpose
Fenfluramine is being developed as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome and other epileptic encephalopathies, including Lennox-Gastaut syndrome. Most patients with Dravet syndrome receive multiple antiepileptic drugs, making it challenging for caregivers to track correct administration times. The present Phase I study was conducted to determine the effect of food on the pharmacokinetic properties of fenfluramine.Methods
Healthy nonsmoking subjects aged 18 to 50 years were enrolled in an open-label, crossover, Phase I pharmacokinetic and safety profile study and received 2 single 0.8-mg/kg doses of ZX008 (fenfluramine hydrochloride oral solution), 1 after a 10-hour overnight fast and the other 30 minutes after the start of consumption of a high-fat breakfast, in a randomly assigned order. A washout period of at least 9 days separated the 2 treatment periods. Venous blood samples were taken before each dose and periodically for 72 hours after each dose for determination of concentrations of fenfluramine and its active metabolite norfenfluramine. Plasma pharmacokinetic parameters were estimated for each subject by noncompartmental analysis.Findings
In the 13 subjects completing both treatment periods, food had no effect on the rate or extent of absorption and bioavailability of fenfluramine as assessed by fed vs fasted adjusted geometric mean observed plasma Cmax (59.1 vs 56.7 ng/mL; NS) and AUC0–∞ (1640 vs 1600 ng?·?h/mL; NS). Additionally, there was no impact of food on systemic exposure of norfenfluramine. Seven subjects reported at least 1 treatment-emergent adverse event; all treatment-emergent adverse events were mild in severity.Implications
The bioequivalence and tolerability of single 0.8-mg/kg oral doses of ZX008 in the fed and fasted states support ZX008 administration without regard to meals. 相似文献11.
Xuehua Ke Abhishek Kavati Debra Wertz Qing Huang Liya Wang Vincent J. Willey Judith J. Stephenson Benjamin Ortiz Reynold A. Panettieri Jonathan Corren 《Clinical therapeutics》2018,40(7):1140-1158.e4
Purpose
The objective of this study was to examine patient characteristics, treatment patterns, and exacerbations among patients with asthma newly treated with omalizumab.Methods
Data for this study were obtained from administrative claims and medical records. The index date was the date of the first claim for omalizumab. All patients had ≥12 months of continuous health plan eligibility before and after the index date. Demographic and clinical characteristics were obtained 12 months before the index date. Treatment patterns of asthma medications, including omalizumab, and asthma exacerbations were evaluated in the preindex and postindex periods.Findings
The study included 1564 patients. Asthma-related medication use decreased from the preindex to the postindex periods (oral corticosteroids, 83.3%–66.4%, P < 0.001; inhaled corticosteroids [ICSs], 33.1%–26.8%, P < 0.001; long-acting β2-adrenergic agonists [LABAs], 6.6%–5.2%, P?=?0.009; ICS-LABA combination, 69.3%–64.3%, P < 0.001; leukotriene modifiers, 67.8%–59.7%, P < 0.001). The proportion of patients with any asthma exacerbations decreased by 33.6% (66.6%–44.2%, P < 0.001). Notably, the relative decreases in hospitalization and emergency department exacerbations were 79.3% and 72.2%, respectively. A total of 930 patients (59.5%) discontinued omalizumab treatment during the entire postindex period (maximum, 3400 days [approximately 9 years]), with 353 (38.0%) restarting omalizumab treatment.Implications
In this real-world analysis, patients newly initiating omalizumab therapy for allergic asthma used fewer concomitant asthma medications, while experiencing significant reductions in asthma exacerbations, especially hospitalization- and emergency department–specific exacerbations, from pre– to post–omalizumab treatment initiation periods. 相似文献12.
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13.
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14.
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15.
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16.
Maral DerSarkissian Patrick Lefebvre Kruti Joshi Brianne Brown Marie-Hélène Lafeuille Rachel H. Bhak Michael Hellstern Priyanka Bobbili Brian Shiner Antoine C. El Khoury Yinong Young-Xu 《Clinical therapeutics》2018,40(9):1496-1508
Purpose
The aim of this article was to describe and compare treatment patterns, health care resource utilization (HRU), and health care costs before and after transition in veterans with schizophrenia who were transitioned from paliperidone palmitate given once monthly (PP1M) to paliperidone palmitate given every 3 months (PP3M) according to prescribing-information guidelines.Methods
This retrospective, longitudinal study was conducted using electronic health records data from the Veterans Health Administration (VHA). Veterans were eligible for inclusion if they were aged 18years or older, had ≥1 dispensation of PP3M, were enrolled with VHA benefits for ≥24 months prior to transition to PP3M, had ≥1 schizophrenia diagnosis, were transitioned to PP3M according to prescribing-information guidelines (operationalized as no gap in PP1M treatment of >45days during the 4 months prior to PP3M transition, with the same dosage in the last 2 PP1M dispensations), and had appropriate dose conversion. Treatment patterns, HRU, and costs 6 months pre and post PP3M transition were described and compared using the McNemar test and the Wilcoxon signed rank test.Findings
Of the 277 veterans identified, the majority were men (92.8%); the median age was 56.5years. Among 197 veterans who had at least 6 months of follow-up pre and post PP3M transition, oral antipsychotic use was significantly decreased (from 49.7% to 43.1%; P?=?0.0326). Additionally, the mean number of days spent in an inpatient setting (41.4vs 21.6; P?=?0.0164), the mean number of outpatient visits per patient (31.0vs 25.6; P < 0.0001), and the mean total health care costs ($27,745vs $23,772; P?=?0.0050) were significantly decreased.Implications
After transitioning to PP3M treatment, veterans had significantly reduced use of oral antipsychotics, HRU, and costs. Although generalizability may be limited due to the veteran population and to those who transitioned according to PP3M prescribing guidelines, future studies in other patient populations may be used to extend these conclusions. 相似文献17.
Mi-Kyeong Kim Sook Young Lee Hae-Sim Park Ho Joo Yoon Sang-Ha Kim Young Joo Cho Kwang-Ha Yoo Soo-Keol Lee Hee-Kyoo Kim Jung-Won Park Heung-Woo Park Jin-Hong Chung Byoung Whui Choi Byung-Jae Lee Yoon-Seok Chang Eun-Jung Jo Sang-Yeub Lee You Sook Cho Choon-Sik Park 《Clinical therapeutics》2018,40(7):1096-1107.e1
Purpose
The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone.Methods
This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n?=?112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n?=?116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, asthma control test score, and the frequency of rescue medication used during the treatment period.Findings
Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, –0.98 [0.06] vs –0.81 [0.06]; P?=?0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV1, FVC, FEV1/FVC, and asthma control test score changes from baseline for the 2 treatment groups. Montelukast/levocetirizine was well tolerated, and the safety profile was similar to that observed in the montelukast group.Implications
The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667. 相似文献18.
Mami Uchida Hitoshi Kawazoe Shingo Takatori Hiroyuki Namba Ryuji Uozumi Akihiro Tanaka Hiromu Kawasaki Hiroaki Araki 《Clinical therapeutics》2018,40(7):1214-1222.e1
Purpose
Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy.Methods
This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors.Findings
A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non–RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18–0.99]; P?=?0.048).Implications
The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy. 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.
Eric Lawitz Mohamed Bidair Thomas Marbury Christopher T. Jones Avantika Barve Baldur Magnusson David T. Barkan Ursula Bodendorf Kathryn Bracken Erica Canino Darlene Chen Kristina Dabovic Tycho Heimbach Marjorie Ison Catherine L. Jones Steven J. Kovacs Jay P. Lakshman Bin Li Richard A. Colvin 《Clinical therapeutics》2018,40(9):1567-1581.e4