Bioequivalence study of levofloxacin tablets in healthy Indian volunteers using HPLC

An improved HPLC method was developed and validated for the determination of concentration of levofloxacin (CAS 100986-85-4) in human plasma. This paper is an attempt to compare the bioavailability of two levofloxacin tablet formulations (reference and test) containing 500 mg of levofloxacin. Both the formulations were administered orally as a single dose, separated by a washout period of 1 week. The HPLC method was validated by examining the precision and accuracy for the inter-day and intra-day runs in a linear concentration range of 0.10-10.00 microg/ml. Bioequivalence of two formulations were determined in 12 healthy, Indian, male volunteers in a single-dose, two-period, two-sequence, two-treatment crossover study. The content of levofloxacin in plasma was determined using HPLC with UV detection. The formulations were compared using the following pharmacokinetic parameters: area under the plasma concentration-time curve (AUC(o-t)), area under the plasma concentration-time curve from zero to infinity (AUC(o-infinity)), peak plasma concentration (C(max)), and time to reach peak plasma concentration (t(max)). The results indicated that there were no statistically significant differences (P > 0.05) between the logarithmically transformed AUC(o-infinity), and C(max) values of the test and reference formulations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(o-t), AUC(o-infinity) and C(max) were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 99.98% of that of the reference formulation.     

LC-MS/MS法研究氢溴酸东莨菪碱口腔速崩微囊片在比格犬体内的药代动力学

研究氢溴酸东莨菪碱口腔速崩微囊片在比格犬体内的药代动力学和生物等效性。液相色谱分离采用C18柱(100 mm×3.0 mm,3.5μm),甲醇-2 mmol.L-1甲酸铵溶液(25∶75)为流动相;质谱检测采用ESI离子源,正离子MRM方式检测。将6只比格犬随机分成2组,分别单剂量灌服氢溴酸东莨菪碱口腔速崩微囊片(受试制剂)和氢溴酸东莨菪碱普通片(参比制剂)0.6 mg,定时采集血样,测定比格犬体内的血药浓度并计算药代动力学参数。受试制剂和参比制剂的Cmax分别为(8.16±0.67)、(3.54±0.64)ng.mL-1;t1/2分别为(2.83±0.45)、(3.85±0.82)h;tmax分别为(1.25±0.27)、(0.42±0.09)h;AUC0-12 h分别为(25.06±3.75)、(9.59±1.02)h.ng.mL-1;AUC0-∞分别为(26.30±3.92)、(10.80±1.45)h.ng.mL-1;MRT0-12 h分别为(3.38±0.34)、(3.86±0.26)h;MRT0-∞分别为(3.98±0.63)、(5.37±1.00)h。受试制剂和参比制剂在AUC和吸收速率方面具有...     

Variable omeprazole kinetics in healthy Jordanian adults

OBJECTIVES: The objective of this study was to examine the pharmacokinetics of orally administered omeprazole in healthy adult Jordanian men. METHOD: Plasma concentrations of omeprazole were measured over a 12 h period after administration of a single oral dose of 40 mg omeprazole (Losec), AstraZeneca, UK). Subjects were healthy adult Jordanian men age 18-38 (24 +/- 4, mean +/- SD). The pharmacokinetic parameters were derived from the plasma concentration-time profiles for AUC(0-t), AUC(0-inf), C(max), t(max), t(1/2e) and K(e). RESULTS: The pharmacokinetic of omeprazole were scattered over a wide range. The median AUC(0-inf) was 784.86 +/- 1182.88 (ng.h/ml), and the median C(max) was 521 +/- 354 (ng/ml) (median +/- SD). In general, most subjects showed normal distribution (approximately 90%). Some subjects (10%) did show very high AUC and C(max) compared with the reported AUC and C(max) levels. These subjects had higher half-lives and lower rates of elimination. CONCLUSION: Significant difference in the pharmacokinetics of omeprazole after a single dose administration was noted. Approximately 10% of the study group showed very high omeprazole plasma levels and AUCs. Differences in the pharmacokinetics might be due to differences in the genetic make-up of subjects.     

福多司坦在健康受试者体内的药代动力学

目的研究健康受试者单剂量及多剂量口服福多司坦片后的药代动力学特征。方法36名健康受试者随机分为高、中、低3个剂量组，每组12人，男女各半，分别单剂量口服福多司坦片600，400和200 mg；中剂量组受试者单次口服福多司坦400 mg后，经过1周清洗期，再每日3次，每次400 mg，连续服药5 d。测定血浆中福多司坦的浓度，计算药代动力学参数。结果高、中、低3个单剂量组福多司坦的消除半衰期及体内平均驻留时间相近，AUC_{0-10 h}和C_max均与剂量呈线性关系；男性受试者的T_max，C_max和AUC均小于女性受试者，T_1/2均大于女性受试者。统计学结果表明男性与女性间C_max和AUC的差异与性别无关，而与体重有关。中剂量组多次给药后的平均稳态血药浓度为(4.1±0.8) μg·mL^-1，消除半衰期为(2.5±0.4) h。结论剂量在200～600 mg时，福多司坦在健康受试者体内呈线性药代动力学特征，多剂量给药与单剂量给药的药代动力学参数基本一致。     

C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 (MDR1) gene and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed for 14 healthy subjects. Blood cyclosporine concentrations were measured by HPLC. Concentration-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the C3435T polymorphism of MDR1 gene using the PCR and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the Mann-Whitney U test according to his or her P-gp genotype. There were seven (7) homozygous C/C, six (6) C/T, and one (1) homozygous T/T genotypes in these 14 healthy volunteers. According to their genotypes, mean t(max) 1.6 +/- 0.3 hours, mean C(max) 1337 +/- 329 ng/mL, mean Cl/F 66.5 +/- 18.3 L/h, and mean AUC 5642 +/- 1577 ng.h/mL in C/C group and mean t(max) 2.0 +/- 0.6 hours, mean C(max) 1540 +/- 721 ng/mL, mean Cl/F 55.2 +/- 18.9 L/h, and mean AUC 6902 +/- 1405 ng.h/mL in C/T+T/T group. Although Cmax and AUC in C/T and T/T group were 15% and 22% larger than those in C/C group, none of these parameter comparisons was statistically significant. There were no statistical differences in cyclosporine pharmacokinetics among different MDR1 genotypes in these 14 healthy subjects.     

替米沙坦在中国健康志愿者体内的药代动力学特征

目的　通过对健康志愿者口服不同剂量替米沙坦片后的药代动力学研究 ,探讨替米沙坦在国人体内的药代动力学特征。方法　 9名中国健康男性志愿者按拉丁方设计分别口服三种单剂量替米沙坦片 (4 0、80、12 0mg) ,用高效液相色谱荧光检测法测定血浆替米沙坦浓度 ,采用 3P97软件拟合药代动力学参数。结果　受试者血药浓度随其单剂量给药量的增加呈现非比例的升高趋势 ,计算所得的药动学参数显示 ,口服 4 0、80、12 0mg替米沙坦片的AUC0～ 96分别为(895 0 3± 36 4 5 3)、(30 30 34± 14 5 4 80 )和 (135 70 4 4±35 5 1 5 4 ) μg·h-1·L-1;Cmax 分别为 (6 0 71± 2 8 10 )、(2 14 0 5± 74 14 )和 (978 32± 2 34 89) μg·L-1,不同剂量组的AUC0 t/dose、Cmax/Dose比值间差异有显著性 (P <收稿日期 :2 0 0 4-0 4-2 6,修回日期 :2 0 0 4-0 5 -2 9作者简介 :熊玉卿 ( 195 7-) ,女 ,博士 ,教授 ,研究方向 :药物代谢及药代动力学 ,Tel:0 791 63 60 65 4,E mail:xyq112 6@yahoo .com .cn0 0 1)。结论　替米沙坦在中国人体内过程 (剂量范围为 4 0～ 12 0mg)显示非线性药代动力学特征     

Pharmacokinetics and bioequivalence of haloperidol tablet by liquid chromatographic mass spectrometry with electrospray ionization

The purpose of this study is to investigate the bioequivalence of two haloperidol 5 mg tablets, Myung In haloperidol (Myung In Pharm. Co., Ltd., test drug) and Peridol (Whanin Pharm. Co., Ltd., reference drug), and also to estimate the pharmacokinetic parameters of haloperidol in Korean volunteers. The bioavailability and pharmacokinetics of haloperidol tablets were examined on 24 healthy volunteers who received a single oral dose of each preparation in the fasting state in a randomized balanced 2 way crossover design. After an oral dosing, blood samples were collected for a period of 60 h. Plasma concentrations of haloperidol were determined using a liquid chromatographic electrospray mass spectrometric (LC-MS) method. The pharmacokinetic parameters were calculated with noncompartmental pharmacokinetic analysis. The geometric means of AUC0-60h and Cmax between test and reference formulations were 17.21 +/- 8.26 ng x h/mL vs 17.31 +/- 13.24 ng x h/mL and 0.87 +/- 0.74 ng/mL vs 0.85 +/- 0.62 ng/mL, respectively. The 90% confidence intervals of mean difference of logarithmic transformed AUC0-60h and Cmax were log0.9677 - log1.1201 and log0.8208-log1.1981, respectively. It shows that the bioavailability of test drug is equivalent with that of reference drug. The geometric means of other pharmacokinetic parameters (AUCinf, t1/2, Vd/F, and CL/F) between test drug and reference drug were 21.75 +/- 8.50 ng x h/mL vs 21.77 +/- 15.63 ng x h/mL, 29.87 +/- 8.25 h vs 29.60 +/- 7.56 h, 11.51 +/- 5.45 L vs 12.90 +/- 6.12 L and 0.26 +/- 0.09 L/h vs 0.31 +/- 0.17 L/h, respectively. These observations indicate that the two formulation for haloperidol was bioequivalent and, thus, may be clinically interchangeable.     

Anidulafungin does not require dosage adjustment in subjects with varying degrees of hepatic or renal impairment

Two open-label studies assessed the effects of hepatic and renal impairment on anidulafungin pharmacokinetics. A single 50-mg dose was administered intravenously to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to normal healthy controls. Anidulafungin was well tolerated. AUC, CL, C(max), t(max), t(1/2), and V(ss) between renally impaired subjects and controls were not significantly different (P>.05), and no measurable amounts of drug were found in dialysate. The same pharmacokinetic parameters were also not affected (P>.05) by mild or moderate hepatic insufficiency, with respective mean AUCs of 50.6 +/- 11.7 microg x h/mL and 68.6 +/- 14.5 microg x h/mL, compared to 70.0 +/- 13.4 microg x h/mL in controls. Statistically significant decreases (P<05) of AUC (33% change) and C(max) (36% change) in severely hepatically impaired subjects compared to controls--most likely secondary to ascites and edema--were not clinically relevant. Anidulafungin can be safely administered to patients with any degree of hepatic or renal impairment without dosage adjustment and without regard to hemodialysis schedules.     

Pharmacokinetics of felodipine extended-release tablets in healthy Taiwanese subjects: a retrospective review

The objective of this study was to investigate the pharmacokinetics of felodipine (CAS 72509-76-3) in healthy male Taiwanese subjects. This is a retrospective review of five felodipine pharmacokinetic studies completed in Taiwan. A total of 100 evaluable healthy Taiwanese males were enrolled in these studies. The subjects received 5 mg (n = 80) or 10 mg (n = 20) of Plendil (felodipine extended-release tablets; felodipine ER) once daily for 6 days. The mean +/- SD t(max,ss,) CG(max,ss) and AUG(tau) of dose normalized to 10 mg felodipine was 3.32 +/- 1.33 h, 13.12 +/- 5.34 nmol/L and 136.33 +/- 63.18 nmol x h/L, respectively. By using Kolmogorov-Smirnov's test and probit plots, the results indicated that the frequency distribution of AUC/dose, C(min)/dose and CL/F was bimodal. Compared to data from the literature, the mean C(max,ss) and AUG(tau) of 5 mg felodipine in healthy young Taiwanese subjects were similar to or slightly lower than data from Swedish, Danish, Turkish and Canadian studies in healthy young subjects who received 10 mg felodipine. Comparable C(max) values and approximately 30% lower AUC values were observed when comparing the 5 mg Taiwanese data to data in healthy elderly German subjects who also received 5 mg felodipine. Taiwanese subjects might have lower CYP3A4 activity to metabolize felodipine, which is similar to the phenomenon observed with nifedipine.     

Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: an open-label, pharmacokinetic interaction clinical trial

The effects of the CYP3A4 inducer, Hypericum perforatum, on the pharmacokinetics of a single oral dose of ivabradine were assessed. An open-label, 2-period, nonrandomized, phase-I, pharmacokinetic interaction design was used. Twelve healthy volunteers received a single oral dose of ivabradine (10 mg) followed by H perforatum (300 mg orally, 3 times a day) for 14 days, combining the last dose with another single dose of ivabradine. Pharmacokinetic data for ivabradine (S16257) and its main active metabolite (S18982) prior to and after the administration of H perforatum were analyzed. After repeated administration of H perforatum, highest observed concentration in plasma (C(max)) and area under the concentration-time curve (AUC) were significantly decreased for ivabradine (32.7 +/- 16.6 vs 15.4 +/- 7.0 ng/mL, P < .01; 114 +/- 39.1 vs 43.7 +/- 12.0 ng x h/mL, P < .01, respectively), and for S18982 (C(max), 6.8 +/- 3.7 vs 5.1 +/- 2.0 ng/mL, P < .05; AUC, 56.2 +/- 23.4 vs 38.3 +/- 25.1 ng x h/mL, P < .01). Tendencies toward shorter time to C(max) and lower apparent terminal half-life values were found. Pharmacokinetic results are consistent with an induction of ivabradine metabolism by H perforatum.     

琥珀酸索利那新片在中国健康受试者的生物等效性研究

目的:评价中国健康受试者空腹及餐后单次口服琥珀酸索利那新受试制剂和参比制剂的生物等效性。方法:采用单中心、随机、开放、两周期交叉设计,空腹组和餐后组受试者各24例,每周期口服受试制剂或参比制剂10 mg,采用LC-MS/MS法测定索利那新血药浓度,WinNonlin 7.0软件计算药动学参数,并进行生物等效性评价。结果:空腹组受试制剂与参比制剂的药动学参数分别为:C max(13.99±3.34)和(13.27±3.20)ng/mL,AUC 0-t(675.60±210.46)和(653.31±238.59)h·ng·mL^-1,AUC 0-∞(728.28±240.20)和(718.14±275.63)h·ng·mL^-1,t max(5.00±1.41)h和(4.98±1.07)h,t 1/2(39.19±9.29)和(42.44±12.66)h,相对生物利用度按AUC 0-t计算为105.06%,按AUC 0-∞计算为104.07%。餐后组受试制剂与参比制剂的药动学参数分别为:C max(15.65±5.30)和(15.02±4.42)ng/mL,AUC 0-t(808.85±271.19)和(793.76±256.78)h·ng·mL^-1,AUC 0-∞(917.02±347.82)和(875.49±310.77)h·ng·mL^-1,t max(4.29±1.48)h和(5.69±4.10)h,t 1/2(49.47±20.08)和(45.29±12.24)h,相对生物利用度按AUC 0-t计算为100.91%,按AUC 0-∞计算为102.97%。空腹/餐后条件下两制剂的主要药动学参数C max、AUC 0-t、AUC 0-∞几何均数比值的90%置信区间均在80.00%~125%。结论:琥珀酸索利那新的受试制剂和参比制剂在空腹和餐后条件下,均生物等效。     

A simple high-performance liquid chromatographic method for the determination of acyclovir in human plasma and application to a pharmacokinetic study

A rapid, simple and sensitive reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the measurement of acyclovir (CAS 59277-89-3) concentrations in human plasma and its use in bioavailability studies is evaluated. The method was linear in the concentration range of 0.05-4.0 microg/ml. The lower limit of quantification (LLOQ) was 0.05 microg/ml in 0.5 ml plasma sample. The intra- and inter-day relative standard deviations across three validation runs over the entire concentration range were less than 8.2%. This method was successfully applied for the evaluation of pharmacokinetic profiles of acyclovir capsule in 19 healthy volunteers. The main pharmacokinetic parameters obtained were: AUC(o-t) 6.50 +/- 1.47 and 7.13 +/- 1.44 microg x h/ml, AUC(0-infinity) 6.77 +/- 1.48 and 7.41 +/- 1.49 microg x h/ml, C(max) 2.27 +/- 0.57 and 2.27 +/- 0.62 microg/ml, t(1/2) 2.96 +/- 0.41 and 2.88 +/- 0.33 h, t(max) 0.8 +/- 0.3 and 1.0 +/- 0.5 h for test and reference formulations, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration--time curve for acyclovir. 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of acyclovir were included in the bioequivalence range (0.8-1.25 for AUC).     

Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in healthy volunteers. Three doses of either 750 mg or 1000 mg levofloxacin were administered intravenously to 4 healthy adult subjects (750 mg) to 20 healthy adult subjects divided into five groups of 4 subjects (1000 mg). Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Levofloxacin was measured in plasma, BAL fluid and alveolar cells (ACs) using a sensitive and specific combined high-performance liquid chromatographic tandem mass spectrometric technique (HPLC/MS/MS). Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. The maximum plasma drug concentration to minimum inhibitory concentration ratio (C(max)/MIC(90)) and the area under the drug concentration curve to minimum inhibitory concentration ratio (AUC/MIC(90)) during the dosing interval were calculated for potential respiratory pathogens with MIC(90) values from 0.03 microg/mL to 2 microg/mL. In the 1000 mg dose group, the C(max) (mean+/-standard deviation (S.D.)), AUC(0-8h) and half-life were: for plasma, 9.2+/-1.9 microg/mL, 103.6 microg h/mL and 7.45 h; for ELF, 25.8+/-7.9 microg/mL, 279.1 microg h/mL and 8.10h; and for ACs, 51.8+/-26.2 microg/mL, 507.5 microg h/mL and 14.32 h. In the 750 mg dose group, the C(max) values in plasma, ELF and ACs were 5.7+/-0.4, 28.0+/-23.6 and 34.2+/-18.7 microg/mL, respectively. Levofloxacin concentrations were significantly higher in ELF and ACs than in plasma at all time points. For pathogens commonly associated with community-acquired pneumonia, C(max)/MIC(90) ratios in ELF ranged from 12.9 for Mycoplasma pneumoniae to 859 for Haemophilus influenzae, and AUC/MIC(90) ratios ranged from 139 to 9303, respectively. The C(max)/MIC(90) ratios in ACs ranged from 25.9 for M. pneumoniae to 1727 for H. influenzae, and AUC/MIC(90) ratios ranged from 254 to 16917, respectively. The C(max)/MIC(90) and AUC/MIC(90) ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of community-acquired respiratory pathogens.     

Pharmacokinetics and urinary excretion of eprosartan in Chinese healthy volunteers of different gender

The study aims to evaluate the pharmacokinetics and urinary excretion of eprosartan in Chinese healthy volunteers and to study the effect of gender on pharmacokinetics of eprosartan. Twenty healthy volunteers (ten men and ten women) were recruited for an open trial and received a single dose of 600 mg eprosartan. Using a validated LC/MS/MS method, plasma and urinary concentrations of eprosartan were determined. The following pharmacokinetic parameters were elucidated after administration: the area under the plasma concentration versus time curve from 0 to 32 h (AUC0-32h) 14818.75 +/- 7312.11 ng x h/mL, the area under the plasma concentration versus time curve from 0 to infinite (AUC(0-infinity)) 15081.62 +/- 7379.63 ng x h/mL, peak plasma concentration (Cmax) 3664.25 x 1653.94 ng x h/mL, time to Cmax (Tmax) 1.63 +/- 0.46 h, elimination half-life (t(1/2)) 8.03 +/- 4.04 h, apparent clearance (CL/F) 47.84 +/- 19.21 L/h, apparent volume of distribution of the central compartment (V/F) 537.21 +/- 287.91 L, renal clearance (CLr) 1.33 +/- 0.41 L/h, amount of unchanged eprosartan excreted into urine 18.44 +/- 6.43 mg and fraction of unchanged eprosartan excreted into urine 3.07 +/- 1.07%. Our results also indicated that no gender differences were observed in the pharmacokinetics of eprosartan in Chinese healthy volunteers.     

Pharmacokinetics of naftidrofuryl in patients with renal impairment

Naftidrofuryl (CAS 31329-57-4) is used, mainly in elderly patients, in the treatment of various vascular disorders. The aim of this study was to evaluate and compare the pharmacokinetics of naftidrofuryl after single oral administration of a 200 mg naftidrofuryl tablet (Praxilene) in caucasian male and female subjects with renal impairment versus healthy volunteers. This prospective and open study was conducted in three parallel groups: Group A = healthy subjects with a Cl(CR) > 80 ml/min, Group B = uraemic patients with a 20 < or = Cl(CR) < 40 ml/min, Group C = uraemic patients with a Cl(CR) < 20 ml/min. Blood samples were taken over a period of 32 h after dosing. The mean values (+/-SD) of the pharmacokinetic parameters of naftidrofuryl for group A were as follows: tmax: 1.3 h (median), Cmax: 174 +/- 46 ng/ml, t(1/2 beta): 4.4 +/- 1.1 h, AUC(0-infinity): 1541 +/- 384 ng x h/ml; for group B: tmax: 2.5 h (median), Cmax: 239 +/- 94 ng/ml, t(1/2 beta): 5.0 +/- 1.2 h, AUC(0-infinity): 2361 +/- 751 ng x h/ml; for group C: tmax: 3.0 h (median), Cmax: 236 +/- 104 ng/ml, t(1/2 beta): 5.0 +/- 2.1 h, AUC(0-infinity): 2488 +/- 2003 ng x h/ml. The statistical analysis was performed on the pharmacokinetic parameters with one-way ANOVA in order to compare each group. No significant difference between each group was observed. In conclusion, renal insufficiency did not appear to influence the pharmacokinetic profile of oral naftidrofuryl.     

细胞色素P450 CYP2C9*3对格列本脲和氯诺昔康中国人体药代动力学的影响

目的研究人体内细胞色素P450 2C9酶突变等位基因CYP2C9*3对格列本脲和氯诺昔康药代动力学的影响。方法采用PCR-RFLP方法对83名无血源关系的受试者进行CYP2C9*3等位基因的筛查，基因型为CYP2C9*1/*3(n=7)和*1/*1(n=11)的受试者分别参加了格列本脲和氯诺昔康的人体药代动力学试验。采用LC/MS/MS法分别测定受试者口服格列本脲(2.5 mg)和氯诺昔康(8 mg)后不同时刻血浆中格列本脲和氯诺昔康的浓度。结果两组受试者口服格列本脲后，CYP2C9*1/*3组AUC_0-∞显著增加，为CYP2C9*1/*1组的1.5倍，CL/F降低了40%；两组受试者口服氯诺昔康后，CYP2C9*1/*3组AUC_0-∞亦显著增加，为CYP2C9*1/*1组的2.2倍，CL/F降低了55%。结论CYP2C9酶的突变等位基因CYP2C9*3对格列本脲和氯诺昔康的药代动力学有显著性影响。     

替米沙坦胶囊正常人体相对生物等效性研究

目的:研究替米沙坦胶囊正常人体相对生物等效性。方法:20名健康男性志愿受试者单剂量随机交叉口服替米沙坦胶囊(受试制剂)或替米沙坦片(参比制剂)80mg,采用高效液相色谱法测定血药浓度,以3p97程序计算药动学参数和相对生物等效性。结果:受试制剂与参比制剂在体内血药浓度均呈二室模型,tmax分别为(2.08±1.64)、(2.02±0.86)h,Cmax分别为(2.10±1.36)、(1.95±1.08)μg/ml,AUC0～t分别为(116.25±55.97)、(123.94±65.66)(μg·h)/ml,t1/2β分别为(74.23±25.11)、(79.18±23.27)h。经配对t检验,受试制剂与参比制剂药动学参数无显著性差异(P>0.05),受试制剂相对于参比制剂的生物利用度为(93.80±12.24)%。结论:2种制剂具有生物等效性。     

Bioequivalence studies of tacrolimus capsule under fasting and fed conditions in healthy male and female subjects

The bioequivalence of tacrolimus (CAS 104987-11-3) 5 mg capsules was assessed in two single-dose, open-label, randomIzed 2-way crossover trials with a minimum washout period of 14 days; one trial was conducted under fasting condition (n = 44) and the other one under fed condition (n = 48). Blood samples were collected over a 120-h period and concentrations were assayed using a liquid chromatography tandem mass spectrometry (LCMS/MS) method. A non-compartmental method was used for calculation of pharmacokinetic parameters. Under fasting conditions, mean AUC(0-t), AUC(0-inf) and C(max) were comparable between the test (296 ng x h/mL, 318 ng x h/mL and 32 ng/ mL, respectively) and the reference formulations (289 ng x h/mL, 309 ng x h/mL and 33 ng/mL, respectively). T(max) was reached between 1.5 and 2 h post-dose. Mean AUC(0-t), AUC(0-inf) and C(max) were also comparable under fed conditions (154 ng x h/mL, 169 ng x h/mL and 7.6 ng/mL, respectively, for the test and 161 ng x h/mL, 176 ng x h/mL and 7.5 ng/mL, respectively, for the reference formulation). Under fed conditions, T(max) was reached between 5 and 6 h post-dose. 90% geometric confidence intervals were all within the acceptable 80-125% limit, suggesting bioequivalence between the generic product and the innovator product.     

Dose proportionality of reboxetine enantiomers in healthy male volunteers.

Reboxetine is a racemic mixture of FCE 22071 and FCE 21684 enantiomers. The pharmacokinetics of the enantiomers of reboxetine were observed to be linear in male healthy subjects (n = 6) after the administration of 1.5, 3, 4.5 mg dose of reboxetine as solutions. Kinetic analysis was based on chiral HPLC assay of the enantiomers in plasma collected up to 72 h after each administration. C(max) and AUC were more than double for FCE 22071 (C(max): 38.3+/-13.5, 76. 6+/-26.3, 99.8+/-24.1 ng/mL and AUC(infinity): 605.8+/-233.2, 1288. 3+/-796.4, 1780.7+/-669.3 ng. h/mL for 1.5, 3, 4.5 mg, respectively) than for FCE 21684 (C(max): 15.2+/-5.3, 34.6+/-14.0, 43.1+/-12.3 ng/mL and AUC(infinity): 247.0+/-103.9, 529.1+/-278.4, 773.0+/-355.3 ng. h/mL), whatever the administered dose. The half-lives of the enantiomers were similar (FCE 22071: 13.1, 11.0, 12.6 h and FCE 21684: 12.8, 11.2, 12.2 h after 1.5, 3, 4.5 mg, respectively) and not substantially affected by the dose level.     

Pharmacokinetics and comparative bioavailability of two terbinafine hydrochloride formulations after single-dose administration in Chinese healthy subjects

The bioavailability of a new terbinafine (CAS 91161-71-6) preparation was compared with a commercially available original preparation (reference) of the drug in 19 Chinese healthy male volunteers. The study was performed in an open, randomized, single blind two-sequence, two-period crossover design. Under fasting conditions, each subject received a single oral dose of 250 mg terbinafine as a test or reference formulation with a 7-day washout period between the two preparations. The plasma concentrations of terbinafine were analyzed by a sensitive liquid chromatography-ultraviolet spectrometry method. The pharmacokinetic parameters included AUC(0-t) AUC(0-infinity), C(max), t1/2, and T(max). The values of AUC(0-t) demonstrated nearly identical bioavailability of terbinafine from the examined formulations. The AUC(0.48) of terbinafine was 5982.85 +/- 2449.17 and 6761.63 +/- 3140.33 ng x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (C(max)) of terbinafine was 1656.25 +/- 623.18 ng/ml for the test and 1552.07 +/- 660.35 ng/ml for the reference product, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration time curve for terbinafine. The 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of terbinafine were within the bioequivalence range (80%-125% for AUC). This study shows that the test formulation is bioequivalent to the reference formulation of terbinafine.