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1.
AIMS
In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed.METHODS
For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n = 19) or matching placebo (n = 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day.RESULTS
When co-administered with ketoconazole, mean Cmax and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean Cmax and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l.CONCLUSIONS
Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan''s effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output. 相似文献2.
Rüdiger Nave Atef Halabi Rolf Herzog Peter Schaffer Jörg Diefenbach Stephan Krause Peter Berghöfer Gezim Lahu Manfred Hartmann 《European journal of clinical pharmacology》2013,69(5):1149-1155
Purpose
Teduglutide is a recombinant analogue of human glucagon-like peptide-2 that has recently been approved for the treatment of short bowel syndrome in adults. This study was designed to study the influence of renal function and age on teduglutide pharmacokinetics.Methods
This was an open-label study with six parallel groups (6 subjects each). Three groups with renal impairment (moderate, severe and end-stage renal disease) were compared to healthy subjects with normal renal function, which were matched to the renal-impaired subjects with respect to demographics. At least two elderly subjects (≥65 years) were enrolled per group. A single dose of 10 mg teduglutide was subcutaneously administered to each subject. Teduglutide plasma concentrations were measured using a validated liquid chromatography method with tandem mass spectrometric detection, and the primary pharmacokinetic variables (AUCinf and Cmax) were calculated.Results
Area under the concentration versus time curve extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of teduglutide in subjects with end-stage renal disease were approximately 2.59- and 2.08-fold higher, respectively, than those of healthy subjects. The AUCinf and Cmax were also slightly higher in subjects with moderate and severe renal impairment. Comparison of healthy subjects aged <65 years with healthy elderly subjects revealed very similar pharmacokinetics in both subgroups.Conclusions
In our study population, the primary pharmacokinetic parameters of teduglutide increased with increased severity of renal impairment. These results suggest that the daily dose of teduglutide should be reduced by 50 % in patients with moderate and severe renal impairment and end-stage disease. We found no effect of age on the pharmacokinetics of teduglutide in healthy subjects. The treatment was well tolerated, and there were no safety concerns. 相似文献3.
Tianli Wang Kyle Baron Wei Zhong Richard Brundage William Elmquist 《Pharmaceutical research》2014,31(3):649-659
Purpose
The current study presents a Bayesian approach to non-compartmental analysis (NCA), which provides the accurate and precise estimate of AUC 0 ∞ and any AUC 0 ∞ -based NCA parameter or derivation.Methods
In order to assess the performance of the proposed method, 1,000 simulated datasets were generated in different scenarios. A Bayesian method was used to estimate the tissue and plasma AUC 0 ∞ s and the tissue-to-plasma AUC 0 ∞ ratio. The posterior medians and the coverage of 95% credible intervals for the true parameter values were examined. The method was applied to laboratory data from a mice brain distribution study with serial sacrifice design for illustration.Results
Bayesian NCA approach is accurate and precise in point estimation of the AUC 0 ∞ and the partition coefficient under a serial sacrifice design. It also provides a consistently good variance estimate, even considering the variability of the data and the physiological structure of the pharmacokinetic model. The application in the case study obtained a physiologically reasonable posterior distribution of AUC, with a posterior median close to the value estimated by classic Bailer-type methods.Conclusions
This Bayesian NCA approach for sparse data analysis provides statistical inference on the variability of AUC 0 ∞ -based parameters such as partition coefficient and drug targeting index, so that the comparison of these parameters following destructive sampling becomes statistically feasible. 相似文献4.
Xiaoli Wang Sabiha Mondal Jessie Wang Giridhar Tirucherai Donglu Zhang Rebecca A. Boyd Charles Frost 《Am J Cardiovasc Drugs》2014,14(2):147-154
Background
Activated charcoal is commonly used to manage overdose or accidental ingestion of medicines. This study evaluated the effect of activated charcoal on apixaban exposure in human subjects.Methods
This was an open-label, three-treatment, three-period, randomized, crossover study of single-dose apixaban (20 mg) administered alone and with activated charcoal given at 2 or 6 h post-dose to healthy subjects. Blood samples for assay of plasma apixaban concentration were collected up to 72 h post-dose. Pharmacokinetic parameters, including peak plasma concentration (C max), time to C max (T max), area under the concentration–time curve from time 0 to infinity (AUCINF), and terminal half-life (T ½), were derived from apixaban plasma concentration–time data. A general linear mixed-effect model analysis of C max and AUCINF was performed to estimate the effect of activated charcoal on apixaban exposure.Results
A total of 18 subjects were treated and completed the study. AUCINF for apixaban without activated charcoal decreased by 50 and 28 %, respectively, when charcoal was administered at 2 and 6 h post-dose. Apixaban C max and T max were similar across treatments. The mean T ½ for apixaban alone (13.4 h) decreased to ~5 h when activated charcoal was administered at 2 or 6 h post-dose. Overall, apixaban was well tolerated in this healthy population, and most adverse events were consistent with the known profile of activated charcoal.Conclusion
Administration of activated charcoal up to 6 h after apixaban reduced apixaban exposure and facilitated the elimination of apixaban. These results suggest that activated charcoal may be useful in the management of apixaban overdose or accidental ingestion. 相似文献5.
Matthias Hoch Petra Hoever Rudolf Theodor Jasper Dingemanse 《European journal of clinical pharmacology》2013,69(6):1235-1245
Purpose
To characterise further the previously observed cytochrome P450 3A4 (CYP3A4) interaction of the dual orexin receptor antagonist almorexant.Methods
Pharmacokinetic interactions were investigated (n?=?14 healthy male subjects in two treatment groups) between almorexant at steady-state when administered either concomitantly or 2 h after administration of single doses of simvastatin (40 mg) or atorvastatin (40 mg).Results
Almorexant dose-dependently increased simvastatin exposure (AUC0–∞) when administered concomitantly [geometric mean ratios (90 % CI): 2.5 (2.1, 2.9) (100 mg), 3.9 (3.3, 4.6) (200 mg)], but not Cmax [3.7 (3.0, 4.5) for both doses]. Time-separated administration resulted in relevant reductions of the interaction [AUC0–∞: 1.4 (1.2, 1.7) (100 mg), 1.7 (1.5, 2.0) (200 mg); Cmax: 1.5 (1.3, 1.9) (100 mg), 1.9 (1.6, 2.4) (200 mg)]. Similar results were obtained for hydroxyacid simvastatin. Independent of almorexant dose and relative time of administration, AUC0–∞ and Cmax of atorvastatin increased (ratios ranged from 1.1 to 1.5). AUC0–∞ and Cmax of o-hydroxy atorvastatin decreased dose-independently [AUC0–∞: 0.8 (0.8, 0.9) (100 mg), 0.6 (0.5, 0.6) (200 mg); Cmax: 0.3 (0.3, 0.4) (100 mg), 0.2 (0.2, 0.3) (200 mg)] when atorvastatin was concomitantly administered. Cmax of o-hydroxy atorvastatin slightly decreased (0.8 for both doses) following time-separated administration; AUC0–∞ was unchanged.Conclusions
Whereas almorexant increased simvastatin exposure dose- and relative time of administration-dependently, atorvastatin exposure increased to a smaller extent and irrespective of dose and time. This suggests that the observed interaction of almorexant with simvastatin is mainly caused by intestinal CYP3A4 inhibition, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition. 相似文献6.
Matthias Hoch Petra Hoever Federica Alessi Rudolf Theodor Jasper Dingemanse 《European journal of clinical pharmacology》2013,69(3):523-532
Purpose
Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates.Methods
Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9.Results
Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4–5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0–1.4], 1.4-fold (90 % CI 1.2–1.6), and 1.3-fold (90 % CI 1.2–1.4) in the maximum plasma concentration (Cmax), area under the concentration–time curve from time 0 to infinity (AUC0-∞), and terminal half-life (t1/2), respectively, of midazolam; the time to peak plasma concentration (tmax) was unchanged. Whereas Cmax and tmax were not influenced by almorexant, the AUC0-∞ of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1–1.4) and the t1/2 by 1.3-fold (90 % CI 1.0–1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0–3.7) and 3.4-fold (90 % CI 2.6–4.4) in Cmax and AUC0-∞, respectively, for simvastatin; the t1/2 and tmax were unchanged. The Cmax and AUC0-∞ of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3–3.5 and 2.2–3.5, respectively; the tmax increased by 2 h and the t1/2 was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant.Conclusions
Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level. 相似文献7.
Miao Yan Ping-Fei Fang Huan-De Li Ping Xu Yi-Ping Liu Feng Wang Hua-Lin Cai Qin-You Tan 《European journal of clinical pharmacology》2013,69(3):515-521
Purpose
To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of talinolol, a probe drug for P-glycoprotein (P-gp) activity in humans.Methods
Fourteen healthy adult male subjects were enrolled in a two-phase randomized crossover-design study. In each phase the volunteers received placebo or compound glycyrrhizin tablets (75 mg glycyrrhizin three times daily) for 6 days. On the seventh day, a single oral dose of 100 mg talinolol was administered, and blood samples were obtained to determine plasma talinolol concentrations, measured in plasma by high-performance liquid chromatography with an ultraviolet detector. Non-compartmental analysis was used to characterize talinolol plasma concentration–time profiles. All pharmacokinetics parameters were calculated using DAS ver. 2.1 software, and statistical analyses were performed with SPSS ver. 13.0 software. Analysis of variance was used to check the difference of the means of the pharmacokinetic parameters between the two treatments at a significance level of 0.05.Results
All treatments were well tolerated during the study period. The geometric mean ± standard deviation of the AUC0–∞ for talinolol treated by glycyrrhizin and talinolol treated by placebo was 2,218.3?±?724.3 and 1,988.2?±?649.2 ng·h/mL, respectively. The 90 % confidence intervals for the ratio of adjusted geometric means (glycyrrhizin:placebo) for AUC0–∞ and C max fell wholly within the interval [80, 125]. Six days of glycyrrhizin treatment resulted in no significant alterations in the pharmacokinetic parameters (AUC0–∞, AUC0–24, C max, t max, t ½) for talinolol.Conclusions
Continuous glycyrrhizin administration had no induction effect on the expression of P-gp in our trial. Further research is needed to study the direct inhibition effect of glycyrrhizin on the function of P-gp with the simultaneous administration of both glycyrrhizin and P-gp substrate. 相似文献8.
Kosoglou T Reyderman L Kasserra C Jennings LK Young S Xuan F Pei J Maxwell SE Schiller J Meehan AG Cutler DL 《European journal of clinical pharmacology》2012,68(3):291-300
Background
Vorapaxar, a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 (PAR-1).Methods
Since race/ethnicity may affect the safety, efficacy and dosage of drugs, this study was conducted to evaluate potential differences in the pharmacodynamics, pharmacokinetics and safety of vorapaxar after single (5, 10, 20, or 40?mg) or multiple (0.5, 1, or 2.5?mg once daily) doses in healthy Japanese and matched (gender, age, height, and weight) Caucasian volunteers.Results
Vorapaxar was well tolerated in both Japanese and Caucasian subjects. Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial/ethnic groups were similar. In both racial groups, complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40?mg and was consistently achieved and maintained with a 2.5?mg daily maintenance dose.Conclusion
There were no substantial differences in the safety, pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects. 相似文献9.
Anil Patel Tarang Shah Gaurang Shah Vijay Jha Chinmoy Ghosh Jagruti Desai Bakulesh Khamar Dr Bhaswat S. Chakraborty 《Am J Cardiovasc Drugs》2010,10(2):95-103
Background
The Polycap? (polypill; aspirin [acetylsalicylic acid], ramipril, simvastatin, atenolol, and hydrochlorothiazide) was found to be safe and effective for reducing multiple cardiovascular risk factors in The Indian Polycap? Study (TIPS).Objective
We evaluated the bioavailability of each ingredient of the Polycap? and determined any drug-drug interactions relative to single component reference preparations.Methods
The bioavailability of the ingredients of the Polycap? (T; test) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately (R; reference) in a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatographytandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte.Results
Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80–125% for peak plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUCt), and AUC from time zero to infinity (AUC∞). The T/R ratio for Cmax, AUCt and AUC∞ was within 80–125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose-normalized salicylic acid. However, for simvastatin, the T/R point estimates for Cmax, AUCt and AUC∞ for Ln-transformed data were significantly lower (~3–4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher (~25–35%) than the higher bound of 125%. Thus, the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin.Conclusion
The Polycap? was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap? is safe (no serious adverse events) and well tolerated, and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well preserved. 相似文献10.
Purpose
The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD).Methods
Forty healthy individuals [18–45?years (young); ≥65?years (elderly); ten men, ten women per age group) received 200?mg ticagrelor.Results
Ticagrelor was rapidly absorbed [time to maximum concentration (Cmax) (tmax) 2.5–3.0?h], and its major active metabolite, AR-C124910XX rapidly formed (tmax 3.0–3.5?h) in all groups. Ticagrelor exposure was higher in elderly vs. the young [area under the curve from time 0 to infinity (AUC0-∞) 52%; Cmax 63% higher] and women vs. men (AUC0-∞ 37%; Cmax 52% higher). Mean terminal elimination half-life was slightly longer in women vs. men but was unaffected by age. Similar results were observed for AR-C124910XX (elderly vs. young, AUC0-∞ 48%; Cmax 61% higher), and in women vs. men (AUC0-∞ 55%; Cmax 56% higher). Across all groups, ticagrelor produced substantial final-extent inhibition of platelet aggregation (IPA): >90% at 4 and 8?h postdose. Individuals with highest ticagrelor exposure (i.e., elderly) had the lowest IPA, indicating an age-related platelet sensitivity effect. In young individuals, platelet sensitivity was greater in men vs. women. Ticagrelor tolerability was not affected by age or gender.Conclusions
Systemic exposures to ticagrelor and AR-C124910XX were higher in elderly vs. young and in women vs. men. Age- and gender-related changes in IPA were apparent, but substantial IPA was achieved in all groups. No adjustment in ticagrelor dose should be considered necessary based on age and gender. 相似文献11.
David S. Small Prajakti Kothare Eunice Yuen D. Richard Lachno Ying G. Li Kenneth J. Winters Nagy A. Farid Lan Ni Joseph A. Jakubowski Daniel E. Salazar Vivian T. Thieu Christopher D. Payne 《European journal of clinical pharmacology》2010,66(2):127-135
Purpose
Prasugrel is a novel thienopyridine prodrug metabolised to an active metabolite that binds irreversibly to the platelet P2Y12 receptor and inhibits adenosine diphosphate (ADP)-induced platelet aggregation. We compared prasugrel pharmacokinetics, pharmacodynamics, and tolerability in healthy Chinese, Japanese, Korean and Caucasian subjects.Methods
In an open-label, single-centre, parallel-design study, 89 healthy subjects (25 Chinese, 20 Japanese, 22 Korean and 22 Caucasian) aged 20–65 years were given a prasugrel 60-mg loading dose (LD) followed by daily 10-mg maintenance doses (MD) for 7 days and then 5-mg MD for 10 days. Plasma concentrations of prasugrel’s active metabolite and inhibition of ADP-induced platelet aggregation (IPA) were determined.Results
Mean exposure to prasugrel’s active metabolite in all treatment regimens was higher in each of the Asian groups than in the Caucasian group, although there was considerable overlap between individual exposure estimates in Asians and Caucasians. The mean IPA was also higher in Asians than in Caucasians following a prasugrel 60-mg LD, although the difference did not consistently achieve statistical significance. Prasugrel 10-mg or 5-mg MD produced statistically significantly higher IPA in each Asian group compared with that in the Caucasians. Prasugrel was well tolerated during the LD and MD regimens by all groups.Conclusions
Mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10-mg or 5-mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition. 相似文献12.
Qin-You Tan Huan-De Li Rong-Hua Zhu Qi-Zhi Zhang Jun Zhang Wen-Xing Peng 《Am J Cardiovasc Drugs》2013,13(1):17-25
Background and Objectives
Ranolazine was approved by the US Food and Drug Administration in January 2006 for the treatment of chronic angina pectoris, and is the first approved agent from a new class of anti-anginal drugs in almost 25 years. The primary objective of this study was to determine the concentration of ranolazine in human plasma using the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method and to compare the pharmacokinetic properties of ranolazine after administration of single and multiple doses of ranolazine in healthy Chinese adult volunteers.Methods
A randomized, open-label, single- and multiple-dose study design was used in the study. Subjects were randomized to receive a single dose of 500, 1,000, or 1,500 mg of ranolazine. Those who received the single dose continued on to the multiple-dose phase and received 500 mg twice daily for 7 days. In the single-dose phase, blood samples were collected from 0 to 48 h after drug administration. In the multiple-dose phase, samples were obtained before drug administration at 8:00 am and 8:00 pm on days 6 and 7 to determine the minimum steady-state plasma concentration (Cmin,ss) of ranolazine; on day 8, samples were collected from 0 to 48 h after drug administration. All values were expressed as means (standard deviations [SDs]). Adverse events (AEs) were monitored throughout the study via subject interview, vital signs, and blood sampling.Results
The LC-MS/MS method was developed and validated. Twelve Chinese subjects (six men, six women) were enrolled in the single-dose phase of the pharmacokinetic study. The mean (SD) age of the subjects was 24.7 (1.6) years; their mean (SD) weight was 61.3 (6.4) kg, their mean (SD) height was 165.7 (4.5) cm, and their mean (SD) body mass index was 21.6 (6.6) kg/m2. The main pharmacokinetic parameters [mean (SD)] for ranolazine after administration of a single oral dose of 500, 1,000, and 1,500 mg were as follows: maximum plasma concentration (Cmax) 741.5 (253.0), 1,355.0 (502.0), and 2,328.7 (890.5) ng/mL, respectively; area under the concentration–time curve from time zero to 48 h (AUC48) 9,071.9 (3,400.0), 16,573.5 (6,806.2), and 29,324.5 (10,857.2) ng·h/mL; AUC from time zero extrapolated to infinity (AUC∞) 9,826.7 (3,152.0), 16,882.4 (6,790.8), and 29,923.5 (10,706.3) ng·h/mL; time to reach Cmax (tmax) 5.3 (1.4), 4.2 (1.2), and 5.9 (2.8) h; elimination half-life (t½) 6.4 (3.3), 6.4 (3.5), and 6.7 (4.3) h. Mean (SD) values for the main pharmacokinetic parameters for ranolazine after administration of multiple doses were as follows: steady-state Cmax (Cmax,ss) 1,732.9 (547.3) ng/mL; Cmin,ss 838.1 (429.8) ng/mL; steady-state AUC at time t (AUCss,(t)) 14,655.5 (5,624.2) ng·h/mL; average steady-state plasma drug concentration during multiple-dose administration (Cav,ss) 1,221.3 (468.7) ng/mL; tmax 3.46 (1.48) h; t½ 6.28 (2.48) h.Conclusion
In this group of healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t½ was independent of the dose. The pharmacokinetic properties of ranolazine were linear after administration of single oral doses of 500 to 1,500 mg. Compared with the pharmacokinetic parameters of the subjects who received a single dose, those who received multiple doses (twice daily) of ranolazine had a larger AUC from time zero to the time of the last measurable concentration (AUClast), AUC∞, Cmax, and apparent total body clearance of drug from plasma after oral administration (CL/F), and shorter tmax (all p < 0.05). Furthermore, some of the main pharmacokinetic parameters of ranolazine may reflect ethnic differences. This dosage was generally well tolerated by all the subjects. 相似文献13.
Li Young Ahn Sung Eun Kim SoJeong Yi Jasper Dingemanse Kyoung Soo Lim In-Jin Jang Kyung-Sang Yu 《Am J Cardiovasc Drugs》2014,14(5):377-385
Background and objectives
Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan after administration of multiple doses to healthy Korean male subjects.Methods
A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study.Results
The concentration–time profile of macitentan was characterized by slow absorption (median time to maximum plasma concentration [t max] 9–10 h) and slow elimination (mean elimination half-life [t ½] 11–15 h). After repeated doses of 3, 10, and 30 mg of macitentan over the course of 10 days, the peak concentration (C max) increased as the dose increased and the area under the plasma concentration–time curve during the dosing interval (AUC τ ) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than macitentan, its mean half-life was 46–48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events.Conclusion
Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations. 相似文献14.
Introduction:
Acute heart failure syndrome (AHFS) is one of the leading causes of hospital admission in the US. Tolvaptan is a vasopressin V2 receptor antagonist that blocks the effect of arginine vasopressin (AVP) in reabsorbing water from the collecting ducts of the nephrons in congestive heart failure.Aims:
To review the evidence for utilizing tolvaptan in the treatment of AHFS.Evidence review:
Several clinical trials have sought to assess the clinical effects of tolvaptan in heart failure. Compared with placebo, tolvaptan has been shown to reduce bodyweight and improve serum sodium in patients with AHFS without worsening renal function. Tolvaptan appeared to be well tolerated with a good safety profile. It caused a significant reduction in pulmonary capillary wedge pressure compared with placebo, but has yet to demonstrate reversal of cardiac remodeling. A large-scale mortality trial showed no differences in long-term mortality rates between tolvaptan and placebo, although early symptom relief was apparent with tolvaptan and lower diuretic use.Place in therapy:
Tolvaptan has shown to be safe and effective in treating congestion in AHFS. Free water excretion in fluid-overloaded patients vulnerable to cardiorenal compromise with standard diuretic therapy makes V2 vasopressin receptor blockade an attractive adjunct to standard medical therapy aimed at reducing congestion in AHFS. 相似文献15.
Hee Youn Choi Yo Han Kim Mi Jo Kim Yook-Hwan Noh Shi Hyang Lee Kyun-Seop Bae Hyeong-Seok Lim 《Am J Cardiovasc Drugs》2014,14(1):63-72
Background and Objective
Valsartan, an angiotensin receptor blocker, is often used with calcium channel blockers (CCBs) such as amlodipine to control hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective of this study was to compare the pharmacokinetic (PK) characteristics of S-amlodipine and valsartan when administered as one tablet each of Exforge and AGSAV301 to healthy male subjects.Methods
This was a single-dose, randomized, open-label, two-way, two-period crossover study. Each subject received a single dose of AGSAV301 and Exforge, separated by a 3-week washout period. Plasma samples for the PK analysis of valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. Tolerability was also evaluated.Results
A total of 29 subjects were enrolled; 24 completed this study. The S-amlodipine maximum plasma concentration (C max) geometric mean ratio (GMR) between AGSAV301 and Exforge was 0.951 (90 % CI 0.983–1.014), and area under the concentration–time curve from time 0 to last measured time point (AUClast) was 0.917 (90 % CI 0.861–0.976). The GMR of valsartan C max was 0.994 (90 % CI 0.918–1.076), and the AUClast was 0.927 (90 % CI 0.821–1.047). All adverse events (AEs) were resolved without sequelae; no serious AEs were reported. Two drugs showed similar tendencies to lower blood pressure in healthy subjects.Conclusions
The PK profiles of AGSAV301 and Exforge were bioequivalent. Both drugs were also well tolerated, with comparable AE profiles and similar blood pressure-lowering tendencies in healthy volunteers, suggesting equivalent therapeutic indications. 相似文献16.
Wen H. Lin Hwa-Ping Feng Craig R. Shadle Terry O’Reilly John A. Wagner Joan R. Butterton 《European journal of clinical pharmacology》2014,70(9):1107-1113
Purpose
The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE).Methods
A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days.Results
Coadministration of boceprevir with EE/NE did not affect NE AUC0–24 but slightly reduced NE C max. Geometric mean ratios (GMRs) for NE AUC0–24 and C max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90 % confidence interval (CI), 0.87–1.06) and 0.83 (90 % CI, 0.76–0.90). Coadministration of boceprevir with EE/NE reduced EE AUC0–24 and C max by 26 and 21 %, with GMRs of 0.74 (90 % CI, 0.68–0.80) and 0.79 (90 % CI, 0.75–0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained <1 ng/ml during the luteal phase. Adverse events reported in this study were consistent with the well-established safety profile of boceprevir.Conclusion
Serum progesterone, LH, and FSH levels indicate that ovulation was suppressed during coadministration of boceprevir with EE/NE. Coadministration of boceprevir with combined oral contraceptives containing EE and ≥1 mg of NE is therefore unlikely to alter contraceptive effectiveness. The ovulation suppression activity of oral contraceptives containing lower doses of NE, and of other forms of hormonal contraception during coadministration with boceprevir, has not been established. 相似文献17.
Purpose
To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug.Methods
The absorption and disposition kinetics of [3H]cefadroxil were determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil were also determined in both genotypes after 44.5 nmol/g intravenous bolus doses.Results
PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil were not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations.Conclusions
The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs. 相似文献18.
Lee Ann Hodges Alison Hughes Darren Targett Michael J. Durcan 《Pharmaceutical research》2014,31(8):2078-2085
Purpose
To investigate the hypothesis that paracetamol is absorbed faster from a hot drink than from a standard tablet using simultaneous scintigraphic imaging and pharmacokinetic sampling.Methods
Twenty-five healthy male volunteers received both paracetamol formulations in a randomised manner. The formulation administered in the first treatment arm was radiolabelled to allow scintigraphic monitoring. In both treatment arms, blood samples were taken for assessing paracetamol absorption.Results
Following the hot drink, paracetamol absorption was both significantly faster and greater over the first 60 min post-dose compared with the tablet, as evidenced by the median time to reach t0.25?μg/mL of 4.6 and 23.1 min, respectively, and AUC0-60 of 4668.00 and 1331.17 h*ng/mL, respectively. In addition, tmax was significantly shorter for the hot drink (median time = 1.50 h) compared with the tablet (1.99 h). However, Cmax was significantly greater following the tablet (9,077 ng/mL) compared with the hot drink (8,062 ng/mL). Onset of gastric emptying after the hot drink was significantly faster than after the standard tablet (7.9 versus 54.2 min), as confirmed scintigraphically.Conclusions
Compared with a standard tablet, a hot drink provides faster absorption of paracetamol potentially due to more rapid gastric emptying. 相似文献19.
Juan José Torrado María Blanco Magí Farré Pere Roset Alfredo García-Arieta 《European journal of clinical pharmacology》2010,66(6):599-604
Purpose
The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies.Methods
The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and Cmax, but not for tmax (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of Cmax and AUC bioequivalence.Results
The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI Cmax non-chiral: 82.77–96.09, sum of enantiomers: 82.19–98.23; 90% CI AUCt non-chiral: 107.23–115.49, sum of enantiomers: 105.73–121.35). However, the chiral method showed differences in AUC and Cmax that resulted in non-bioequivalence for the individual enantiomers (90% CI Cmax S-ibuprofen: 76.05–91.36, R-ibuprofen: 87.84–113.05; 90% CI AUCt S-ibuprofen: 96.67–105.86, R-ibuprofen: 118.86–142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption.Conclusions
Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption. 相似文献20.
Ivy Song Julie Borland Shuguang Chen Phyllis Guta Yu Lou David Wilfret Toshihiro Wajima Paul Savina Amanda Peppercorn Stephen Castellino David Wagner Louise Hosking Michael Mosteller Justin P. Rubio Stephen C. Piscitelli 《European journal of clinical pharmacology》2014,70(10):1173-1179