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1.
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.
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4.
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5.
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6.
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7.
Tommy Tsang Cheung Joanne Wing Yan Chiu Man Fung Yuen Karen Siu Ling Lam Bernard Man Yung Cheung Hwa-Ping Feng Wendy W. Yeh Jiangdian Wang Wenting Li Xu Min Zhao Zaiqi Wang Shengmei Mu 《Clinical therapeutics》2018,40(5):719-732.e1
Purpose
This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals.Methods
This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants.Findings
Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0–∞ and Cmax increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84–1.01] and 0.98 [0.86–1.09], respectively), whereas grazoprevir AUC0–∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27–1.57] and 1.96 [1.64–2.29]). After repeated administration, the accumulation ratios for AUC0–24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0–24 (Chinese/white participants) were 1.58 (1.03–2.42) and 1.21 (0.76–1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated.Implications
In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-5172 PN022. 相似文献8.
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9.
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10.
Background
Restless legs syndrome (RLS) is a common chronic neurologic disorder. Symptoms are most prevalent during the evening and at night, although daytime symptoms may emerge as the disease progresses. Dopamine agonists are currently considered first-line therapy for moderate to severe idiopathic RLS. Most dopamine agonists have short half-lives and are administered in the evening, shortly before the onset of RLS symptoms. Rotigotine is a non-ergot dopamine receptor agonist that has been specifically developed as a transdermal patch to provide continuous drug delivery over a 24-hour period.Objective
This review details the development of rotigotine, from the preclinical studies that established its pharmacokinetic profile to large-scale clinical trials in patients with RLS. Placebo-controlled trials that demonstrated the efficacy and tolerability of rotigotine are discussed, in addition to open-label studies that investigated long-term therapy.Methods
Studies were identified by a PubMed search using the key word rotigotine in conjunction with restless legs syndrome and by reviewing reference lists of retrieved publications. All clinical trials of rotigotine in RLS published before September 2013 were included.Results
Preclinical studies have established activity of rotigotine as a dopamine receptor agonist, and pharmacokinetic data have shown that transdermal delivery maintains stable plasma levels over 24 hours. Rotigotine has demonstrated efficacy in improving moderate to severe RLS symptoms in randomized, placebo-controlled trials, based on scores on the International RLS Study Group rating scale, the RLS-6 scale, and the Clinical Global Impression–Severity subscale. Results of an open-label extension study suggest that efficacy may be maintained for up to 5 years. A polysomnographic study demonstrated an improvement in periodic limb movement index with rotigotine, and subjective assessments have suggested beneficial effects in terms of amelioration of sleep disturbances. Premature discontinuations from rotigotine treatment have ranged from 8% to 38% in studies of 6 weeks to 12 months in duration; 57% of patients discontinued prematurely during a 5-year study. In each trial, adverse events were typical of dopaminergic stimulation and use of a transdermal patch. The most common adverse events were application-site reactions, with a reported prevalence ranging from 17% (1-month sleep laboratory trial) to 58% (5-year open-label extension study). Clinically significant augmentation was recorded in 39 of 295 patients (13%) receiving rotigotine during the 5-year study, of whom 15 (5%) were receiving a dose within the US Food and Drug Administration–approved range of 1 to 3 mg/24 h.Conclusions
Findings from clinical studies have suggested that rotigotine is efficacious in improving RLS symptoms and is generally well-tolerated. The risk of developing clinically significant augmentation appears to be low. As such, rotigotine represents an important addition for RLS treatment. 相似文献11.
Background
Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated.Objective
This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants.Methods
This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated.Results
Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUCτ,ss) and Cmax at steady state (Cmax,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUCτ,ss and Cmax,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was −0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments.Conclusions
Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631. 相似文献12.
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13.
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14.
David Joseph Michael J. Schobelock Robert R. Riesenberg Bradley D. Vince Lynn R. Webster Abidemi Adeniji Mabrouk Elgadi Fenglei Huang 《Antimicrobial agents and chemotherapy》2015,59(1):498-504
The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC0–24,ss), the steady-state maximum concentration of the drug in plasma (Cmax,ss), and the steady-state concentration of the drug in plasma at 24 h (C24,ss) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.) 相似文献
15.
Ruth Plummer Henk M. Verheul Filip Y. F. L. De Vos Karin Leunen L. Rhoda Molife Christian Rolfo Peter Grundtvig-Sørensen Jacques De Grève Sylvie Rottey Guy Jerusalem Antoine Italiano James Spicer Luc Dirix Carsten Goessl Joseph Birkett Stuart Spencer Maria Learoyd Christopher Bailey Emma Dean 《Advances in therapy》2018,35(11):1945-1964
Introduction
The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.Methods
During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1–5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10–13, 20 mg qd days 14–26; cohort 2, anastrozole 1 mg qd days 10–19; cohort 3, letrozole 2.5 mg qd days 10–38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.Results
Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0–τ decreased by 20% (90% CI 0.71–0.90) and 27% (0.63–0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0–τ increased by 13% (1.06–1.22) and 16% (1.11–1.21), respectively]; however, the 90% CI fell within the 0.7–1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.Conclusions
The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.Funding
AstraZeneca.Clinical Trial Registration
NCT02093351.16.
Qi QiuWenfang Liu MM Jing LiYongxiang Wei MD Kexu YangWei Suo MS Wei WuHaiyan Du PhD Yingchao ZhangGuiping Zhao BS Zijie ZhouYingming Zheng BS Yang Lin 《Clinical therapeutics》2014
Background
Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation.Objective
The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride.Methods
This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration–time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs.Results
Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m2) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) μg/mL, respectively; AUC0–24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · μg/mL; and AUC0–∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · μg/mL. The ranges for t½z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0–24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters.Conclusions
Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0–24 and AUC0–∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546. 相似文献17.
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
Purpose
Infection with hepatitis C virus is the leading cause of infectious disease mortality in the United States. BZF961 is a novel small molecule inhibitor of the hepatitis C virus NS3-4A protease. Here we present the results of a randomized, double-blinded, placebo-controlled, multicentered study in treatment-naïve patients with chronic hepatitis C virus genotype-1 infection.Methods
Patients were enrolled sequentially in 2 parts and treated for 3days. BZF961 was administered as monotherapy (500mg BID for 3 days) or in combination with the cytochrome P450 3A4 inhibitor ritonavir to boost its exposure (BZF961 10, 20, or 50mg QD or BID).Findings
BZF961 was safe and well tolerated in the patients studied with no serious adverse events. There were no appreciable differences in adverse events among patients who received BZF961, BZF961 with ritonavir, or placebo. There was a significant, clinically meaningful reduction in viral load from baseline in patients treated either with BZF961 500mg every 12hours alone or BZF961 50mg every 12hours in combination with ritonavir. Activity against the hepatitis C virus of the lower-dose regimens was apparent but more modest. There were no relevant changes from baseline viral loads in placebo-treated patients.Implications
Coadministration of ritonavir with BZF961 boosted BZF961 exposure (including Cmin, which is the clinically relevant parameter associated with antiviral activity) in a therapeutic range with less variability compared with BZF961 alone. For strategic reasons, BZF961 is no longer under development. 相似文献18.
Xavier Pivot Jean Paul Deslypere Lisa Soyeon Park Michael Jinwoo Kim Wonjae Lee Jeonghyeon Lee 《Clinical therapeutics》2018,40(3):396-405.e4
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19.
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20.
Hyounggyoon Yoo Sang Won Lee Deok Yong Yoon Seo Hyun Yoon Joo-Youn Cho Kyung-Sang Yu In-Jin Jang SeungHwan Lee 《Clinical therapeutics》2021,43(3):526-534.e4
PurposeRanolazine, an inhibitor of late inward sodium current, is an antianginal agent. In this study, the pharmacokinetic (PK) properties and tolerability of single- and multiple-dose ranolazine were compared between healthy Korean and white subjects.MethodsAn open-label, ascending single- and multiple-dose study was conducted with healthy male Korean and white subjects. Subjects were administered 375–750 mg of ranolazine once in a single-dose and twice daily in multiple-dose based on their dose groups. Blood samples for the PK assessment were collected up to 48 h after dosing. The geometric mean ratio and its 90% confidence interval in Korean to white subjects for Cmax, Cmax,ss, AUClast, and AUC0–12h,ss of ranolazine were calculated. A population PK analysis was also performed. Safety profiles were assessed throughout the study.FindingsA total of 70 Korean and 48 white subjects completed the study. Ranolazine exposure was similar between Korean and white subjects in all dose groups; however, ranolazine exposure at 750 mg was observed to increase by up to 29% in Korean subjects compared with that in white subjects. On the basis of previous studies, these differences in ranolazine exposure between the 2 ethnic groups may not result in any clinically significant difference. Furthermore, ethnicity was not significantly correlated with the PK properties of ranolazine in the ranolazine PK model. In addition, no significant difference was found in the safety profile of ranolazine between the 2 ethnic groups.ImplicationsThe PK properties of ranolazine had no clinically significant difference, and no difference was found in the safety profiles of ranolazine between Korean and white subjects. It is anticipated that ranolazine can be administered in Korean subjects without dose adjustment. ClinicalTrials.gov identifier: NCT02817932. 相似文献