共查询到20条相似文献，搜索用时 31 毫秒
1.
Purpose
Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection.Methods
In this randomized, single-dose, crossover study, healthy adults aged 18 to 35 years received single 4-mg doses of somatropin via a needle-free device or SC injection, along with octreotide to suppress endogenous growth hormone production. Blood samples were analyzed for serum somatropin and insulin-like growth factor-1 (IGF-1) concentrations over 24 hours after somatropin dosing. Pharmacokinetic and pharmacodynamic parameters were evaluated by using noncompartmental methods, and bioequivalence was determined based on ln transformation of the AUC0–24, AUC0–∞, Cmax, area under the effect-time curve from time 0 to 24 hours (AUEC0–24), and maximum effect concentration (Emax). Bioequivalence was concluded if the 90% CIs of the needle-free device compared with the SC injection, constructed by using the two 1-sided hypotheses at the α = 0.05 level, for these pharmacokinetic/pharmacodynamic parameters fell within the 80.00% to125.00% regulatory acceptance range.Findings
A total of 57 subjects completed both study periods and were included in the pharmacokinetic analyses. Point estimates (90% CIs) of the geometric mean ratio (needle-free device/SC injection) based on serum somatropin were 1.013 (0.987–1.040) for AUC0–24, 1.012 (0.986–1.038) for AUC0–∞, and 1.200 (1.137–1.267) for Cmax. For IGF-1, baseline-corrected point estimates (90% CIs) were 0.901 (0.818–0.993) for AUEC0–24 and 0.867 (0.795–0.946) for Emax. Non–baseline-corrected values were 0.978 (0.953–1.004) for AUEC0–24 and 0.953 (0.923–0.984) for Emax. Both treatments were well tolerated; blood glucose levels increased in nearly all subjects (98.3%). All adverse events were mild and resolved spontaneously within 24 hours.Implications
Bioequivalence was shown for a single 4-mg dose of somatropin delivered by using a needle-free device compared with SC injection based on ln-transformed AUC0–24 and AUC0–∞ but not ln-transformed Cmax. 相似文献2.
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3.
Crista Johnson-Agbakwu Louise Brown James Yuan Robert Kissling David J. Greenblatt 《Clinical therapeutics》2018,40(1):64-73
Purpose
This study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT1A agonist/5-HT2A antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women.Methods
Healthy female volunteers (N = 24) received 2 single doses of a combined oral contraceptive containing ethinylestradiol 30 μg and levonorgestrel 150 μg, either alone (reference) or preceded by treatment with flibanserin 100 mg once daily for 14 days (test). The 2 treatments were given in randomized order, with a 4-week washout period following the last administration of the first treatment. Plasma concentrations of ethinylestradiol and levonorgestrel were measured over 48 hours after dosing for the determination of pharmacokinetic parameters; the primary end points were Cmax and AUC0–∞ of ethinylestradiol and levonorgestrel.Findings
Of the 24 women enrolled (mean age, 38.0 years), 23 completed the study. Mean (SD) Cmax and AUC0–∞ values of ethinylestradiol were 66.7 (16.3) pg/mL and 693 (268) pg · h/mL, respectively, following the oral contraceptive alone, and 72.7 (25.5) pg/mL and 740 (235) pg · h/mL, respectively, when the oral contraceptive was preceded by flibanserin. In both cases, the 90% CIs of the reference/test ratios of Cmax and AUC0–∞ were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of ethinylestradiol. Similarly, the mean (SD) Cmax and AUC0–∞ values of levonorgestrel were 5.0 (1.6) ng/mL and 52.2 (18.7) ng · h/mL, respectively, with the oral contraceptive alone, and 5.0 (1.6) ng/mL and 53.3 (20.4) ng · h/mL, respectively, following flibanserin; again, in both cases, the 90% CIs of the reference/test ratios were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of levonorgestrel. All adverse events were mild to moderate in intensity (incidence: 12.5% and 70.8% with ethinylestradiol/levonorgestrel treatment alone and following administration of flibanserin, respectively).Implications
Pretreatment with flibanserin 100 mg once daily for 2 weeks did not produce a clinically relevant change in oral contraceptive drug exposure following single-dose administration of ethinylestradiol/levonorgestrel. This finding is relevant to women with hypoactive sexual desire disorder who might prefer oral contraceptives to other forms of birth control. EudraCT No: 2006-006960-46. 相似文献4.
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5.
Ju-Hee Ryu Joo-Il Kim Hyung Son Kim Gyu-Jeong Noh Kyung-Tae Lee Eun Kyoung Chung 《Clinical therapeutics》2017,39(1):138-149
Purpose
Pelubiprofen is a novel nonsteroidal anti-inflammatory, analgesic, and antipyretic drug with at least similar efficacy and better tolerability compared with other nonsteroidal anti-inflammatory, analgesic, and antipyretic drugs such as naproxen and aceclofenac. Eperisone hydrochloride is a centrally acting muscle relaxant that performs by blocking calcium channels. The combined use of pelubiprofen and eperisone hydrochloride is increasingly anticipated to promote the clinical effectiveness of pelubiprofen in relieving musculoskeletal symptoms of osteoarthritis, rheumatoid arthritis, and low back pain. No published data are yet available, however, regarding the pharmacokinetic interactions between these 2 drugs when administered concurrently. The objective of this study was to evaluate any pharmacokinetic interactions between pelubiprofen and eperisone hydrochloride in healthy Korean male volunteers.Methods
This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and orally received either 45-mg sustained-release pelubiprofen, 75-mg sustained-release eperisone hydrochloride, or both as a single dose in each treatment period, with a 7-day washout period between each treatment. Serial blood samples were collected over 24 hours after dosing, and plasma concentrations of each drug and the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen) were determined by using a validated HPLC-MS/MS system. Pharmacokinetic analyses were conducted by using noncompartmental methods.Findings
A total of 24 men (mean ± standard deviation of: age, 29 ± 4 years; weight, 72.5 ± 7.8 kg; body mass index, 23.4 ± 1.9 kg/m2) were enrolled, and 23 participants completed the study. For pelubiprofen, the geometric mean ratios (90% CIs) of Cmax and AUC0–∞ were 1.02 (0.87–1.19) and 0.97 (0.88–1.07), respectively. For the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), the geometric mean ratios (90% CIs) of Cmax and AUC0–∞ were 1.05 (0.98–1.13) and 1.04 (1.01–1.07). For eperisone, the geometric mean ratios (90% CIs) of Cmax and AUC0–∞ were 0.87 (0.67–1.15) and 1.05 (0.85–1.30). None of the study participants experienced serious adverse events during the study.Implications
No clinically significant changes were noted in the pharmacokinetic interactions of pelubiprofen, the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), and eperisone hydrochloride between monotherapy and combination therapy with 45-mg sustained-release pelubiprofen and 75-mg sustained-release eperisone hydrochloride. 相似文献6.
Lin Pan Paula Belloni Han Ting Ding Jianshuang Wang Christopher M. Rubino Wendy S. Putnam 《Advances in therapy》2017,34(9):2071-2082
Introduction
Pirfenidone film-coated tablets were developed to offer an alternative to the marketed capsule formulation. This study assessed the bioequivalence of the tablet and capsule formulations under fed and fasted states.Methods
A Phase I, open-label, randomized, four-treatment-period, four-sequence, crossover pharmacokinetics study (NCT02525484) was conducted. Each subject received an 801-mg single dose of pirfenidone as three 267-mg capsules or one 801-mg tablet under fasted and fed conditions. Pirfenidone plasma C max, AUC0–t and AUC0–∞ were used to assess bioequivalence.Results
Forty-four subjects were randomized to treatment. The 801-mg tablet in the fasted state met bioequivalence criteria [90% confidence intervals (CI) 80.00–125.00%] for the GLSM ratios of natural log-transformed C max, AUC0–t and AUC0–∞. Under fed conditions, the 801-mg tablet met the bioequivalence criteria for AUC0–t and AUC0–∞, but slightly exceeded the bioequivalence criteria for the C max (90% CI of 108.26–125.60%). The tablet C max was approximately 17% higher than that of the capsules. In the fed state, the tablet C max, and both AUC0–t and AUC0–∞ were reduced by 39% and 17%, respectively, relative to the fasted state. The tablet and capsules had acceptable tolerability profiles.Conclusions
The pirfenidone 801-mg tablet met bioequivalence criteria when compared with three 267-mg capsules in the fasted state. The tablet C max was slightly higher relative to capsules in the fed state, but this is not expected to have a clinically meaningful impact on the benefit–risk profile of pirfenidone.Funding
This work was supported by F. Hoffmann-La Roche Ltd.7.
Yunona Khomitskaya Nadezhda Tikhonova Konstantin Gudkov Svetlana Erofeeva Victoria Holmes Brian Dayton Nigel Davies David W. Boulton Weifeng Tang 《Clinical therapeutics》2018,40(4):550-561.e3
Purpose
Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation.Methods
Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC0–t, Cmax, and Cmax/AUC0–t) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed.Findings
Forty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m2). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events.Implications
Bioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239. 相似文献8.
Introduction
Clopacin® (Acino Pharma AG) is a proprietary, besylate salt and lactose-free formulation of the widely-used anti-platelet treatment, clopidogrel. This study aimed to evaluate the bioequivalence of Clopacin® with the originator as reference drug, using a guideline-compliant trial design: open-labeled, randomized, single-dose (clopidogrel 75 mg tablet), two-period, crossover trial in 48 healthy male volunteers, with a 7 day wash-out period.Methods
Plasma samples were collected at intervals and extracted before quantifying clopidogrel concentrations using a fully validated LC–MS/MS method. Bioequivalence of Clopacin® and the reference drug was established by comparison of the primary pharmacokinetic parameters, C max, AUC0–t, and AUC0–∞.Results
The parameter values were similar for the two products (analysis of variance) and provided Clopacin/reference ratios (least squares means) of >90% and 90% confidence intervals (CIs 84.64–105.50%, 90.43–111.22%, 88.75–110.71%, respectively) that were well within the limits set for defining bioequivalence, according to international guidelines. The respective Clopacin® and reference drug values for mean time to maximal plasma clopidogrel concentration (t max) were 0.83 and 0.91 h, and for terminal elimination half-life were 3.99 and 3.51 h. The intra-subject coefficients of variability for maximal plasma clopidogrel concentration (C max), area under the plasma clopidogrel concentration versus time curve, at 48 h (AUC0–t) and extrapolated to infinity (AUC0–∞) were 32.2%, 30.2%, and 28.9% (least square means), respectively, and the respective power values were 99.5%, 97.1%, and 95.3%.Conclusion
This bioequivalence study provided robust clopidogrel pharmacokinetic data that established the bioequivalence of Clopacin® and the reference originator drug.Funding
Acino Pharma AG (formerly Cimex AG)9.
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10.
Wen-Yi Li Guo Yu Renee M. Hogan Rajesh Mohandas Reginald F. Frye Eric Gumpricht John S. Markowitz 《Clinical therapeutics》2018,40(1):103-113.e1
Purpose
The purpose of this study was to compare the bioavailability between 2 milk thistle–containing dietary supplements, Product B and IsaGenesis, in healthy volunteers.Methods
Bioavailability between Product B, originally formulated as a powdered capsule, and IsaGenesis, reformulated as a soft gel, were compared by measuring silybin A and silybin B as surrogate pharmacokinetic markers for differences in absorption and bioavailability. For this randomized, open-label, crossover pharmacokinetic study, 12 healthy volunteers consumed a single-dose serving of each supplement separated by at least a 7-day washout period. Serial blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and analyzed via LC-MS/MS.Findings
Rapid absorption and elimination of silybin A and silybin B have been observed after oral administration of both Product B and IsaGenesis. However, the absorption rate and extent, as indicated by mean the Cmax and mean plasma AUC, were significantly higher for the IsaGenesis soft gel formulation. The dose-corrected mean Cmax was 365% and 450% greater for silybin A and B, respectively, relative to powdered Product B. The time to Tmax was reached, on average, at least 1 hour earlier with IsaGenesis relative to Product B for both silybin A and silybin B.Implications
The IsaGenesis soft gel formulation provided substantially greater absorption and bioavailability of silybin A and silybin B relative to the powdered Product B supplement. ClinicalTrials.gov Identifier: NCT02529605. 相似文献11.
Caiyun Zhao Yuan Lv Xiangyan Li Fang Hou Xuzhu Ma Minji Wei Zisheng Kang Lanqing Cui Yahong Xia Yan Liu Jihong Tian 《Clinical therapeutics》2018,40(6):983-992
Purpose
Nemonoxacin, a nonfluorinated quinolone, has been approved in Taiwan and mainland China for the treatment of bacterial infection. Whether nemonoxacin is associated with the adverse events of other quinolones, such as the risk for QT-interval prolongation, which has led to the withdrawal of several fluoroquinolones from the market, needs to be elucidated.Methods
The effects of nemonoxacin on thorough QT/QTc interval was investigated in this randomized, placebo- and positive-controlled crossover study conducted according to the International Conference on Harmonisation E14 guideline. Forty-eight healthy adults received a single oral dose of nemonoxacin 500 mg (therapeutic dose), nemonoxacin 750 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 cohorts (Williams Latin square design) in the fasted condition. After a 7-day washout, 6 male and 6 female subjects were orally administered a 500-mg dose of nemonoxacin after high-fat food intake. The primary end point was the change in QT interval corrected for heart rate using the Fridericia formula (QTcF). The secondary end point was the change in QT interval corrected for heart rate using the Bazett formula (QTcB).Findings
The study revealed that nemonoxacin was classified as not likely dangerous at the therapeutic dose (500 mg) and as potentially dangerous at the supratherapeutic dose (750 mg). The Tmax of nemonoxacin was 1 to 2 hours after administration, and the elimination half-life was 5 to 7 hours, in the fasted conditions. High-fat food intake had significant effects on the Tmax, Cmax, AUC0–∞, and QT/QTc interval of nemonoxacin compared with these values in the fasted condition. A correlation between QTcF and the plasma drug concentration of nemonoxacin was not observed.Implications
Nemonoxacin at the clinically therapeutic and supratherapeutic doses had a prolongation effect on QT/QTc. ClinicalTrials.gov identifier: NCT03362853. 相似文献12.
Xiaojie Wu Yunfei Li Jing Zhang Yingyuan Zhang Jicheng Yu Guoying Cao Yuancheng Chen Beining Guo Yaoguo Shi Jun Huang Yuran Cao Xiaofang Liu Jufang Wu Mikhail Fedorovich Gordeev Hong Yuan Wen Wang 《Clinical therapeutics》2018,40(2):322-332.e5
Purpose
This study was designed to evaluate the safety and pharmacokinetic profiles of MRX-I tablet, an oxazolidinone antibacterial agent, in healthy Chinese subjects.Methods
The study was composed of 3 sequential periods. Period 1 was a randomized, double-blind, placebo-controlled, sequential ascending dose (50 to 1800 mg) study. Period 2 included one arm as a randomized, open-label, 3-period, 3 × 3 Latin square single-dose study of 300, 600, and 900 mg MRX-I administration and another arm as a crossover study to evaluate high-fat diet effect. Period 3 was a randomized, double-blind, placebo-controlled multiple-dose study with 600 or 800 mg, q12h regimens over 15 days.Findings
MRX-I was rapidly absorbed and reached peak plasma concentration at about 2 hours post dose. The Cmax was 8.07, 12.24, and 15.25 mg/L and the corresponding AUC0?∞ 29.21, 48.27, and 59.60 mg/h/L, in 300-, 600-, and 900-mg dosing groups, respectively. High-fat diet increased the exposure of MRX-I. No discernable drug accumulation was observed after 15 days of continuous drug administration. About 2% of MRX-I was excreted via kidneys in unchanged form. No obvious hematologic toxicity by MRX-I was observed during the entire study. Based on Monte Carlo simulation, 600 or 800 mg BID can produce satisfactory efficacy against methicillin-resistant Staphylococcus aureus.Implications
MRX-I was well tolerated in healthy Chinese subjects (50–1800 mg). No serious or severe adverse effects were observed. MRX-I 600 or 800 mg BID up to 15 days can be recommended in future clinical trials. Chinese Clinical Trial Registration (http://www.chinadrugtrials.org.cn) identifier: CTR20131214. 相似文献13.
Purpose
Our aim was to develop and validate the extrapolative performance of a regression model using a limited sampling strategy for accurate estimation of the area under the plasma concentration versus time curve for saroglitazar.Methods
Healthy subject pharmacokinetic data from a well-powered food-effect study (fasted vs fed treatments; n = 50) was used in this work. The first 25 subjects’ serial plasma concentration data up to 72 hours and corresponding AUC0?t (ie, 72 hours) from the fasting group comprised a training dataset to develop the limited sampling model. The internal datasets for prediction included the remaining 25 subjects from the fasting group and all 50 subjects from the fed condition of the same study. The external datasets included pharmacokinetic data for saroglitazar from previous single-dose clinical studies. Limited sampling models were composed of 1-, 2-, and 3-concentration?time points’ correlation with AUC0?t of saroglitazar. Only models with regression coefficients (R2) >0.90 were screened for further evaluation. The best R2 model was validated for its utility based on mean prediction error, mean absolute prediction error, and root mean square error. Both correlations between predicted and observed AUC0?t of saroglitazar and verification of precision and bias using Bland?Altman plot were carried out.Findings
None of the evaluated 1- and 2-concentration?time points models achieved R2 > 0.90. Among the various 3-concentration?time points models, only 4 equations passed the predefined criterion of R2 > 0.90. Limited sampling models with time points 0.5, 2, and 8 hours (R2 = 0.9323) and 0.75, 2, and 8 hours (R2 = 0.9375) were validated. Mean prediction error, mean absolute prediction error, and root mean square error were <30% (predefined criterion) and correlation (r) was at least 0.7950 for the consolidated internal and external datasets of 102 healthy subjects for the AUC0?t prediction of saroglitazar. The same models, when applied to the AUC0?t prediction of saroglitazar sulfoxide, showed mean prediction error, mean absolute prediction error, and root mean square error <30% and correlation (r) was at least 0.9339 in the same pool of healthy subjects.Implications
A 3-concentration?time points limited sampling model predicts the exposure of saroglitazar (ie, AUC0?t) within predefined acceptable bias and imprecision limit. Same model was also used to predict AUC0?∞. The same limited sampling model was found to predict the exposure of saroglitazar sulfoxide within predefined criteria. This model can find utility during late-phase clinical development of saroglitazar in the patient population. 相似文献14.
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15.
Jianzhong Shentu Huili ZhouXingjiang Hu MS Guolan WuLihua Wu MD PhD Meixiang ZhuYou Zhai MS Yunliang ZhengJian Liu MS 《Clinical therapeutics》2014
Background
Bepotastine is a second-generation histamine1 receptor antagonist that is used in the treatment of allergic rhinitis, urticaria, and pruritus associated with skin disease. A new generic formulation of bepotastine has been developed in China, and information concerning bioavailability and pharmacokinetic properties in the Chinese population has not been reported.Objective
The aim of the present study was to compare the bioavailability and pharmacokinetic properties of 2 tablet formulations of bepotastine, the 10-mg generic formulation (test) and a branded formulation (reference), in healthy male Chinese volunteers to obtain registration approval of the test formulation.Methods
A single-center, open-label, randomized, 2-way crossover study with a 1-week washout period was conducted in 24 healthy male volunteers. Blood samples were collected for 16 hours after a single dose of the 10-mg bepotastine test formulation or the reference formulation. Plasma bepotastine concentrations were determined using a validated LC-MS/MS method. Cmax, Tmax, AUC0–t, AUC0–∞, and t½ were determined using noncompartmental analysis. The formulations were considered bioequivalent if the 90% CIs for the log-transformed Cmax and AUC values were within the predetermined interval of 75% to 133% and 80% to 125%, respectively, according to the guidelines of the China Food and Drug Administration.Results
No significant differences were found in mean (SD) pharmacokinetic parameters between the test and reference drugs, including Cmax (74.81 [9.91] ng/mL vs 78.60 [29.58] ng/mL), AUC0–t (295.55[115.29] ng·h/mL vs 299.17[109.29] ng·h/mL), and AUC0-∞ (305.28 [118.50] ng·h/mL vs 310.90 [112.20] ng·h/mL). The mean (SD) t½ values of the test and reference formulations were 2.53 (0.50) hours and 2.62 (0.41) hours, respectively. The 90% CIs of the treatment ratios for the logarithmic transformed values of Cmax, AUC0–t, and AUC0–∞ were 86.96% to 101.80%, 93.22% to 104.13%, and 92.66% to 103.30%, respectively. All values were within the predetermined bioequivalence range. Two adverse events were reported as neutropenia (1 volunteer [4.2%]) and neutrophilia (1 volunteer [4.2%]). Both adverse events were transient and considered mild by physicians.Conclusion
The test and reference tablets met the regulatory criteria for bioequivalence as defined by the China Food and Drug Administration. Both formulations were well tolerated. Chinese Clinical Trials Registry identifier: ChiCTR-TTRCC-13003723. 相似文献16.
Daniel Du 《Advances in therapy》2018,35(8):1169-1180
Introduction
Nicotine replacement therapy (NRT) benefits smokers who wish to quit; nicotine gum represents one NRT. New formulations of nicotine gum have been developed to consider consumer preferences and needs. A new mint-flavored nicotine gum with a different texture was developed that may provide a more appealing taste and chewing experience. This study evaluated this new nicotine gum (2 and 4 mg strengths) for bioequivalence versus the original flavor sugar-free nicotine gum at corresponding dosages.Methods
All subjects randomized in this crossover study received a single dose of all treatments, i.e., 2 and 4 mg doses of test and reference gums, separated by 2–7 days of washout between treatments. Subjects’ maximal plasma nicotine concentration (Cmax) and extent of nicotine absorption (AUC0–t) following the administration of each treatment were calculated from plasma nicotine concentrations. Ratios of test/reference for Cmax and AUC0–t were calculated to evaluate bioequivalence between the two products.Results
Both 2 and 4 mg doses of the new mint-flavored nicotine gum were bioequivalent to the dose-matched reference product as determined by the ratio of the geometric means and their 90% confidence intervals for Cmax and AUC0–t as well as secondary pharmacokinetic parameters. The safety profiles of the test and reference gums were similar; all treatments were well tolerated.Conclusions
A new mint-flavored nicotine gum with modified taste and texture is bioequivalent to the original flavor sugar-free nicotine gum at both the 2 and 4 mg dosage strengths and has a similar safety profile.Funding
GlaxoSmithKline.Trial Registration
ClinicalTrials.gov identifier NCT01847443.17.
MSc Laura Vásquez MSc José V. Scorza Dagert MD Nelson Vicuña-Fernández MSc Sabrina López PhD Elina Rojas PhD Belén Pérez 《Current therapeutic research》2006,67(3):193-203
Background:
Pentavalent antimony (SbV) has demonstrated therapeuticeffectiveness against clinical manifestations of leishmaniasis, an infection caused by Leishmania, a genus of flagellate protozoa comprising parasites of worldwide distribution. Approximately 1.8 million new cases are reported annually.Objective:
The aim of this study was to assess the pharmacokinetics of the investigational generic SbV, Ulamina (pentachloride of antimony + N-methylglucamine), in healthy adult volunteers.Methods:
In this study, SbV was administered IM as a single 5-mg/kg dose.Blood samples were collected at 0.25, 0.75, 1, 2, 4, 8, 12, and 24 hours after administration; urine samples were collected at 6-hour intervals during the 24-hour postadministration period. Determination of trivalent antimony, SbV, and total antimony concentrations in blood and urine samples was carried out using atomic absorption spectrometry. Clinical history was reviewed and the subjects were monitored before and after administration of SbV using physical examination, weight, and hepatic- and renal-function studies. The pharmacokinetic parameters calculated were Cmax, Tmax, absorption constant (Ka), elimination constant (Kel), AUC2-24h, AUC0-∞, elimination phase (t½β), volume of distribution (Vd), and urinary excretion rate.Results:
Five subjects (3 men, 2 women; mean age, 28 years [range, 18-34 years]) were included in the study. One hour after drug administration the following values were obtained: Cmax, 1.1 μg/mL; Tmax, 1.3 hours; Ka, 1.87 hours; Kel, 0.043 hours; AUC0-24h, 12.26 μg/mL · h; AUC0-∞, 19.84 μg/mL · h; t½β, 17.45 hours; Vd, 6.6 L/kg; and urinary excretion rate, 2.8 μg/h; these were mean values for the entire study group. The single dose was well tolerated by all subjects.Conclusions:
The investigational generic SbV, Ulamina, was associated with linearelimination after IM administration of a single 5-mg/kg dose. A 2-compartment pharmacokinetic model was observed in these volunteers; the mean t½β, was 17.45 hours and the mean Vd was 6.6 L/kg. 相似文献18.
Background
Fenofibrate is a serum lipid-lowering agent used as an adjunct to diet in patients with hypercholesterolemia and hypertriglyceridemia. The new fenofibrate tablet formulation was developed as a pharmaceutical equivalent to the marketed tablet formulation containing 145 mg.Objective
The objective of this study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects.Methods
The study was a randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study in healthy human subjects under fasting conditions. Eligible subjects received each treatment in a crossover manner according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. The predose blood sample was taken within 1 hour before dosing, and serial blood sampling was performed up to 72.0 hours’ postdose. The analysis of plasma samples for concentrations of fenofibric acid, the active metabolite of fenofibrate, was conducted by using a validated LC-MS/MS method. Bioequivalence was to be concluded if the 90% CIs as constructed were within the range of 80% to 125% for Cmax, AUC0–t, and AUC0–∞ for fenofibric acid. Subjects were monitored for safety and tolerability throughout the study.Results
15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m2 were recruited into the study. The 90% CIs for the test/reference mean ratios of the ln-transformed pharmacokinetic variables Cmax, AUC0–t, and AUC0–∞ were within the conventional bioequivalence range of 80% to 125%. Both formulations were well tolerated after a single oral dose in these healthy male subjects.Conclusions
Both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic absorption, and hence were considered bioequivalent. 相似文献19.
Chih-Wei Lin Nael M. Mostafa Dennis L. Andress John J. Brennan Cheri E. Klein Walid M. Awni 《Clinical therapeutics》2018,40(2):242-251
Purpose
The objective of the current analyses was to characterize the pharmacokinetic properties of atrasentan and the exposure-response relationships for the efficacy end point, urinary albumin to creatinine ratio (UACR), and the treatment-emergent adverse event, peripheral edema, during 8 or 12 weeks of treatment.Methods
Results from 3 Phase II, randomized, double-blind, placebo-controlled studies (N = 257) were used for the population pharmacokinetic and exposure-response models. Concentration-time and response data for efficacy and tolerability were analyzed using a nonlinear mixed-effects population analysis and logistic regression approaches.Findings
The pharmacokinetic data were adequately described by a 2-compartment model with first-order absorption and elimination. After weight was accounted for, no clinically meaningful differences were found in CL/F or Vd/F of the central compartment between Western and Japanese patients. Exposure-response analyses confirmed the efficacy of atrasentan in reducing UACR, with an estimated decrease in UACR of ≥37% when the atrasentan dose was 0.75 mg or higher. No significant association between atrasentan exposure and the rate of edema was identified at atrasentan doses of 0.5, 0.75, and 1.25 mg. The rates of peripheral edema were comparable in patients receiving active treatment and placebo.Implications
The exposure-response relationships for efficacy and tolerability were consistent between Western and Japanese patients. On the basis of these analyses, a dose of 0.75 mg/d was selected for the Phase III trial. ClinicalTrials.gov identifiers: NCT01356849, NCT01399580, and NCT01424319. 相似文献20.
Hankil Son Hyerang Roh Donghwan Lee HeeChul Chang JunKu Kim Chohee Yun Kyungsoo Park 《Clinical therapeutics》2013