Relative bioavailability of two 5-mg montelukast sodium chewable tablets: a single dose, randomized, open-label, 2-period crossover comparison in healthy korean adult male volunteers

Montelukast sodium, cysteinyl leukotriene receptor 1 specific antagonist, has been marketed in Korea for the treatment of bronchial asthma and allergic rhinitis. The aim of this study was to compare the pharmacokinetics and relative bioavailability of a test and reference formulation of montelukast 5-mg chewable tablets in healthy Korean male volunteers to meet KFDA regulatory criteria for marketing of the new generic formulation. This study was designed as a single-dose, 2-treatment, and 2-period crossover trial with 32 healthy volunteers. Each subject was randomly assigned to receive the test (Dong-Kook Montelukast Sodium Chewable Tablet 5 mg?) or reference (Singulair Chewable Tablet 5 mg?) formulation. The tablet was chewed 20 times, and then swallowed with 240 mL of water. Plasma concentrations of montelukast up to 24 h after the dose were determined using a validated UPLC-MS/MS method, and the bioequivalence between the 2 formulations was assessed by statistical analysis of mean ratios of log-transformed AUC0-24 h and Cmax. No period or sequence effects were detected. The AUC0-24 h was 1 835 ng·h/mL for the test formulation, and 1 930 ng·h/mL for the reference formulation. The respective values of AUC0-∞ were 1 917 and 2 015 ng·h/mL. The Cmax of the test and reference products (247 and 283 ng/mL, respectively) reached at 2.25 and 2.72 h, respectively. Then, they gradually decreased with the mean terminal t1/2 of 5.25 and 5.30 h for the test and reference products, respectively. The 90% CIs for the ratio of log-transformed AUC0-24 h and Cmax for the test and reference formulations were 0.92-0.99 and 0.83-0.91, respectively. No adverse events were reported in this study. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these fasting healthy Korean male volunteers.     

A comparative bioavailability study of carbamazepine tablets and a chewable tablet formulation

Differences in product formulations have been shown to affect the therapeutic response by altering the relative bioavailability and pharmacokinetics of a drug. The relative bioavailability and pharmacokinetics of carbamazepine tablets (CBZ) and a chewable tablet formulation were evaluated in 10 normal healthy subjects (five men and five women). The study utilized a randomized, crossover design with a 4-week washout period between doses. Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 14, 24, 30, 36, and 48 h following a 200-mg dose. Plasma samples were assayed by fluorescence polarization immunoassay. Ke, Cmax, Tmax, area under the curve (AUC), and relative bioavailability were estimated using traditional pharmacokinetic methods and compared by paired t test. A statistically significant higher Cmax (3.81 +/- 81 vs. 4.64 +/- .80 mg/L) was observed with the chewable tablet formulation but was not thought to be clinically relevant. No significant differences between formulations for Ke (0.022 +/- 0.007 vs. 0.025 +/- 0.008 h-1 h), Tmax (7.49 +/- 2.69 vs. 6.04 +/- 2.7 h), AUC 48 h (119 +/- 22 vs. 133 +/- 13 mg/h/L), or AUCO--infinity ( 221 +/- 40 vs. 203 +/- 41 mg/h/L) were noted. Absorption was variable for both preparations. The relative bioavailability using the tablet as the standard formulation was (0.92 +/- 0.22). Transient, mild side effects were noted in three subjects with the chewable tablet alone, and one subject experienced side effects with both formulations. It was concluded that CBZ tablets and chewable tablets may be used interchangeably; however, considerable intra- and intersubject variability exists, and the need for patient monitoring is emphasized.     

Bioequivalence study of finasteride. Determination in human plasma by high-pressure liquid chromatography coupled to tandem mass spectrometry

Two different finasteride (CAS 98319-26-7) tablet formulations were evaluated for their relative bioavailability (Flaxin tablets 5 mg, as the test formulation vs reference formulation, tablets 5 mg) in 23 healthy male volunteers who received a single 5 mg oral dose of each preparation. The study was open, randomized with a two-period crossover design and a 7-day washout period. Plasma samples were obtained over a 48-h interval. The finasteride concentrations were determined by high-pressure liquid chromatography (HPLC) coupled to tandem mass spectrometry (LC-MS-MS). The analytical method developed has a limit of quantitation (LOQ) of 0.50 ng/ml in plasma. For the quality control the measured concentration was 2.05 +/- 0.14 ng/ml (mean +/- SD, n = 30) with a precision of 6.9% and an accuracy of 2.55% at a concentration of the starting solution of 2.00 ng/ml, while with 20.00 ng/ml starting solution the measured concentrations were 20 +/- 0.80 ng/ml (n = 30) with a precision of 3.81% and an accuracy of 0.09%. From the plasma finasteride concentration vs time curves the following pharmacokinetics parameters were obtained: AUC0-48, AUC0-infinity, Cmax, Cmax/AUC0-48, Ke, elimination half-life and tmax. Geometric mean test/reference formulations individual percent ratio was 95.71 for AUC0-48 h and 88.70% for Cmax. The 90% confidence interval for the geometric mean of the individual ratio test/reference formulations was 95.70-120.20% for AUC0-48 h, 94.60-121.30 for AUC0-infinity and 88.70-108% for Cmax. Since for both Cmax or AUC the 90% Cl values are within the interval proposed by the Food and Drug Administration, the test formulation is bioequivalent to the reference formulation for both the rate and extent of absorption after single dose administration.     

Bioavailability of a new effervescent tablet of diclofenac

OBJECTIVE: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). SUBJECTS AND METHOD: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-infinity and Cmax. RESULTS: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean +/- SD) for DIC-effervesc is 950+/-341 ng/ml (first Cmax) and for DIC-enteric 1364+/-335 ng/ml. The mean AUC0-infinity, (arithm. mean +/- SD) amounts to 1097+/-210 ng/ml x h for DIC-effervesc and 1262+/-220 ng/ml x h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 - 91.3%). DIC-effervesc was well tolerated. CONCLUSION: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragee. A rapid onset of therapeutic effect is postulated in acute pain disorders.     

Pharmacokinetics of extended-release and immediate-release formulations of galantamine at steady state in healthy volunteers

OBJECTIVE: To assess the steady-state galantamine (GAL) bioavailability of the extended-release 24-mg qd capsule (GAL-ER) with and without food and to evaluate the relative bioavailability of GAL-ER with the immediate-release 12-mg bid tablet (GAL-IR) at steady state. METHODS: This was a single-center, open-label, randomized, 3-way crossover study in 24 healthy volunteers (12 males and 12 females) aged 18 to 45 years. After 7 days of GAL-ER 8 mg qd each morning and 7 days of GAL-ER 16 mg qd each morning, subjects received the following treatments in randomized, crossover order (7 days each): GAL-ER 24 mg qd each morning (fasted before Day 7 morning dose), GAL-ER 24 mg qd each morning (fed before Day 7 morning dose), and GAL-IR 12 mg bid (fasted before Day 7). Pharmacokinetic parameters of GAL at steady state were determined after morning intake on Day 7 of each treatment week. Safety evaluations included adverse event (AE) reporting, physical examination, clinical laboratory tests, vital signs, and electrocardiography. RESULTS: The treatment ratios of area under the plasma concentration-time curve of GAL from time 0-24 h post-dosing (AUC24 h), peak plasma concentration (Cmax), and pre-dose plasma concentration (Cmin) for GAL-ER fed/fasting were 105%, 112%, and 103%, respectively. The treatment ratios and 90% confidence intervals for all above mentioned pharmacokinetic parameters demonstrated bioequivalence (with the range of 80-125%), indicating that food had no effect on GAL-ER bioavailability. As anticipated, GAL-ER (fasting) had mean AUC24 h similar to GAL-IR (fasting), with lower Cmax (63 ng/mL vs 84 ng/mL) and longer time to reach Cmax (4.4 h vs 1.2 h). The treatment ratios and 90% confidence intervals for both AUC24 h and Cmin demonstrated bioequivalence (within the range of 80-125%). The treatment ratio for Cmax was 75.7%, indicating a 24% lower Cmax for GAL-ER than for GAL-IR. In this study, GAL-ER was safe and well tolerated with or without food and was comparable to the GAL-IR formulation. CONCLUSION: Food had no effect on the GAL bioavailability of GAL-ER at steady state. GAL-ER was bioequivalent to GAL-IR with respect to AUC24 h and Cmin.     

Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

普罗布考包合物胶囊在家犬体内的药代动力学与相对生物利用度

目的研究普罗布考包合物胶囊在家犬体内的药代动力学与相对生物利用度。方法用高效液相色谱法测定6条健康犬po 250 mg普罗布考片(制剂A)或普罗布考包合物胶囊(制剂B)后不同时间血浆中活性药物的浓度,绘制药-时曲线,计算药代动力学参数及相对生物利用度。结果制剂A和制剂B的药-时曲线符合二室模型,其T_max均为(9.3±2.1) h,C_max分别为(1.5±1.0) μg·mL^-1和(2.3±0.9) μg·mL^-1,AUC_0～240分别为(85±56) μg·h·mL^-1和(134±55) μg·h·mL^-1。以制剂A为参比,制剂B中普罗布考的相对生物利用度为(198±90)%,两种制剂的AUC_0～240有显著性差异(P<0.05)。结论初步分析认为,改善普罗布考的水溶性是提高普罗布考生物利用度的关键因素之一。     

Bioequivalence study of two losartan formulations administered orally in healthy male volunteers

The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.     

Comparative pharmacokinetic and relative bioavailability study of coated and uncoated azithromycin powder for suspension in healthy Bangladeshi male volunteers

Azithromycin (AZT; CAS 83905-01-5) is an efficient antibiotic and is widely prescribed in Bangladesh. The taste of uncoated AZT suspension is bitter. Although several taste masked oral suspensions of AZT are available in Bangladesh, information regarding the bioavailability of these formulations in Bangladeshi population is unavailable. The purpose of this study was to compare the relative bioavailability and other pharmacokinetic properties of two oral formulation of AZT (200 mg/5 ml) suspensions, the uncoated reference product and coated test product (Tridosil 200 mg/5 ml) and to evaluate whether these formulations meet the FDA criteria to assume bioequivalence in Bangladeshi male volunteers. A randomized, single-dose, two-way cross-over, open-label pharmacokinetic study was conducted in 24 healthy male volunteers after administration of a single dose of 500 mg AZT suspension under fasting condition following a washout period of three weeks. Blood samples were collected in different time intervals and analyzed for serum AZT concentration using a validated LC/MS/MS method. The pharmacokinetic parameters were determined by the non-compartmental method. From serum data, the obtained values for test and reference products were 383.21 +/- 11.59 and 432.28 +/- 7.22 ng/ ml for Cmax; 5677.47 +/- 1229.53 and 6144.56 +/- 1098.70 h x ng/ml for AUC(0-120); and 6085.29 +/- 1267.53 and 6694.15 +/- 1222.50 h x ng/ml for AUC(0-infinity), respectively. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for Cmax and AUMC(0-infinity). The 90% confidence intervals of the test formulation/reference mean ratios of the Intransformed Cmax, AUC(0-120) and AUC(0-infinity) mean values were found to be 87.89% to 89.36%, 87.96% to 95.71% and 86.77% to 94.29% respectively. In this single-dose study of AZT, it was found that the test formulation met the regulatory criteria for bioequivalence to the reference suspension formulation.     

Clinical development of an everolimus pediatric formulation: relative bioavailability,food effect,and steady-state pharmacokinetics

The immunosuppressant everolimus used in organ transplantation is formulated as a conventional tablet for adults and a dispersible tablet that can be administered in water for pediatric use. As part of the pediatric clinical development program, the relative bioavailability and food effect for the dispersible tablet were evaluated in healthy adult subjects as a prelude to characterizing the steady-state pharmacokinetics in pediatric kidney allograft recipients. In a randomized, open-label, three-way crossover study, 24 healthy adults received single 1.5-mg oral doses of everolimus as (1) six 0.25-mg dispersible tablets in water, (2) two 0.75-mg conventional tablets, and (3) six 0.25-mg dispersible tablets in water after a high-fat breakfast. Cmax and AUC were evaluated by standard bioequivalence testing to determine relative bioavailability and to quantify the effect of food. In a multicenter open-label efficacy/safety trial, pediatric renal allograft recipients received 0.8 mg/m2 (maximum 1.5 mg) bid everolimus as dispersible tablets in water. Serial trough concentrations over the first week and a steady-state pharmacokinetic profile on day 7 posttransplant were collected in 19 patients ranging from ages 2 to 16 years old. The bioavailability of everolimus from the dispersible tablet was 10% lower relative to the conventional tablet, with a ratio (90% confidence interval) of 0.90 (0.76-1.07). After a high-fat meal, tmax was delayed by a median 2.5 hours, and Cmax was reduced by 50%. Overall absorption, however, was not affected by food inasmuch as the fed/fasting AUC ratio was 0.99 (0.83-1.17). In pediatric patients, steady state was reached between days 3 and 5. The corresponding steady-state parameters were as follows: Cmin, 4.4 +/- 1.7 ng/ml; Cmax, 13.6 +/- 4.2 ng/ml; and AUC, 87 +/- 27 ng.h/ml. Steady-state concentration-time profiles in pediatric transplant patients receiving the dispersible tablet were comparable to those of adult patients receiving the conventional tablet when both were dosed to yield similar trough concentrations. If a pediatric patient is converted from the everolimus dispersible tablet to the conventional tablet, this should be based on a 1:1 milligram switch with subsequent therapeutic drug monitoring to further individualize the dose as needed. The dispersible tablet formulation should be taken consistently either with or without food to minimize fluctuations in exposure over time.     

Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers

The bioavailability of a new cefixime ((6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid, CAS 79350-37-1) tablet preparation (Loprax) was compared with that of a reference preparation of the drug in 24 healthy male volunteers. The trial was designed as an open, randomized, single-blind, two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 400 mg cefixime tablet as a test or reference formulation on 2 treatment days. The treatment periods were separated by a one-week washout period. The plasma concentrations of the drug were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-24h, AUC0-infinity, Cmax, t1/2, and Ke. The mean AUC0-infinity of cefixime was 45008.7 +/- 10989.9 and 45221.3 +/- 2155.7 n x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (Cmax) of cefixime was on average 4746.9 +/- 1284 ng/ml for the test and 4726.3 +/- 1206.9 ng/ml for the reference product. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for test and reference tablets. The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of Cmax, AUC0-infinity and AUC0-24h of cefixime were in the bioequivalence range (94%-112%). Therefore, the two formulations were considered to be bioequivalent.     

Influence of food on the bioavailability of a sustained-release verapamil preparation

The effects of food on the bioavailability of a sustained-release (SR) formulation of verapamil (SR-verapamil; Isoptin SR) were determined in an open, three-way single-dose study involving 12 volunteers receiving (in randomized order) the SR preparation (1 X 240 mg) either fasting or with food and a conventional formulation of verapamil (3 X 80 mg) fasting. Compared with the conventional formulation, SR-verapamil had a reduced Cmax, prolonged tmax, and unchanged t1/2, consistent with its SR formulation. The AUC was 80% of the conventional preparation. Concomitant food administration significantly prolonged the tmax of SR-verapamil from 7.3 +/- 3.4 to 11.7 +/- 6.3 h, but had little effect on Cmax, t1/2, or AUC. Similar results were obtained with the metabolite, norverapamil. Food administration also had little effect on the blood pressure and ECG effects of SR-verapamil. Cautions regarding taking this preparation with food therefore appear to be unnecessary.     

Kinetics of oral trifluoperazine disposition in man

The disposition of trifluoperazine (TFP) was studied in five healthy volunteers following oral administration of a 5 mg tablet. Using a very sensitive GC-MS technique plasma TFP concentrations were measured up until 24 h following drug ingestion. Peak plasma concentrations varied widely (range 0.53-3.09 ng ml-1) and were reached 2.8 +/- 0.5 h following ingestion of the TFP tablet. The apparent terminal elimination half-life of TFP was 12.5 +/- 1.4 h. The area under the plasma concentration-time curve differed widely between subjects (range: 5.9-17.6 ng ml-1 h) suggesting large individual differences in the extent of presystemic TFP elimination.     

5-单硝酸异山梨酯缓释胶囊的人体生物等效性

采用GC法测定 5 单硝酸异山梨酯血浆药物浓度 ,研究 5 单硝酸异山梨酯缓释胶囊相对生物利用度和生物等效性。 18名健康志愿者随机交叉单剂量口服试验药 (T)与对照药 (R) 4 0mg ,测得Cmax分别为 (348 3± 146 8)ng/mL和 (347 9± 2 0 2 4)ng/mL ;Tmax 分别为 (4 7± 1 8)h和(4 6± 1 7)h ;AUC( 0 -n) 分别为 (3 933 2± 142 5 0 )ng h/mL和 (3 6 93 0± 12 39 5 )ng h/mL ;相对生物利用度为 (10 6 6± 16 9) %。 18名志愿者随机交叉多剂量口服T与R ,测得达稳态的Cmax分别为 (2 30 9± 72 4)ng/mL和 (190 9± 6 6 9)ng/mL ;Cmin分别为 (4 2 6± 2 3 5 )ng/mL和 (4 7 4±2 2 1)ng/mL ;AUCSS分别为 (2 939 4± 92 2 1)ng h /mL和 (2 6 6 7 4± 832 9)ng·h /mL ;DF分别为1 6± 0 4和 1 3± 0 3 ;相对生物利用度为 (111 0 2± 2 1 0 5 ) %。经生物等效性分析 ,两制剂在单剂量与多剂量条件下生物等效     

Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs

The single-dose pharmacokinetics and bioavailability of three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg po of ketoconazole as tablet (Ktab) and solution (Ksol) formulations. The dogs received 400 mg po of Ktab and Ksol, and 376 mg iv of an intravenous dose (Kiv). In humans the AUC value for Ksol (62.21 +/- 21.2 microgram X h/ml; mean +/- SD) was significantly greater than for Ktab (50.0 +/- 15.2 micrograms X h/ml; p less than 0.05). Peak serum concentrations (Cmax), time to peak serum concentrations (tmax), t1/2, and the terminal elimination rate constant (kel) did not differ between Ktab and Ksol. This suggests that the administration of Ksol may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected. The mean systemic clearance (CLs) of Kiv in dogs was 2.74 +/- 1.10 mL/min/kg, the volume of distribution at steady state (Vdss) was 0.72 +/- 0.28 L/kg, and the half-life was 2.7 +/- 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of Ktab was 0.50 +/- 0.38, which did not differ statistically from that of Ksol, 0.56 +/- 0.23. The Ksol showed less variability in AUC, Cmax, and F values than did Ktab, and two dogs with low bioavailability with Ktab (0.04 and 0.07) had substantially greater bioavailability with Ksol (F = 0.96 and 0.57, respectively). Evaluation of Kiv in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.     

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.     

Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers

Glucosamine (CAS 66-84-2) hydrochloride is an amino monosaccharide indicated for the treatment of arthrosis, especially osteoarthritis of the knee joint. This study was conducted to assess and compare the pharmacokinetic (PK) properties, bioavailability of a newly developed dispersible tablet formulation (test) of glucosamine hydrochloride with those of an established branded capsule formulation (reference) in healthy Chinese adult male volunteers.This single-dose, randomized, open-label, 2-period crossover study was conducted in 18 healthy Chinese adult male volunteers under fasting condition. Plasma samples were collected at pre-specified times over a 12-h period following administration in each period and analyzed the plasma glucosamine concentrations by Liquid Chromatography coupled with Tandem Mass Spectrometry (LC/MS/MS) method. The mean (SD) PK parameters of Cmax, Tmax, AUC0-12, and AUC0-∞ after administration of the test and reference formulations were, respectively, as follows: Cmax, 907.01 (444.22) vs. 944.40 (429.89) ng/mL, Tmax, 3.03 (0.95) vs. 3.30 (0.99) hours, AUC0-12, 2891.41 (1352.30) vs. 2889.69 (925.48) ng/mL/h, and AUC0-∞, 3029.90 (1321.36) vs. 3091.87 (870.36) ng/mL/h. The mean (SD) t1/2 was 1.10 (0.52) hours for the test formulation and 1.50 (1.17) hours for the reference formulation. On ANOVA, neither period nor sequence effects were observed for any PK properties. The relative bioavailability of the test formulation was 98.3% assessed by AUC0-12. The 90% CIs of glucosamine for the log-transformed ratios of Cmax, AUC0-12, and AUC0-∞ were 78.4-113.9%, 80.8-108.5% and 80.8-105.8%, respectively, meeting the predetermined criteria for bioequivalence of SFDA.     

那格列奈分散片的人体生物等效性研究

目的 研究两种那格列奈片剂的人体相对生物利用度,评价其生物等效性.方法 选择20名健康男性志愿者,按照两制剂两周期的随机交叉试验设计,分别单剂量口服参比制剂(普通片)和受试制剂(分散片),剂量均为120mg,采用液相色谱-串联质谱(LC-MS/MS)法测定其血浆中那格列奈的质量浓度,用DAS1.0软件计算各药物代谢动力学参数并进行生物等效性统计分析.结果 受试制剂和参比制剂的主要药物代谢动力学参数,峰浓度(Cmax)分别为(9.1±1.7)μg/mL和(7.7±2.1)mg/L,达峰时间(tmax)分剐为(0.7±0.3)h和(1.9±1.1)h,0～10 h药时曲线下面积(AUC0-10)分别为(19.7±4.0)mg/(L·h)和(20.8±3.0)mg/(L·h),0～∞药时曲线下面积(AUC0-∞)分别为(20.0±4.1)μg/(mL·h)和(21.3±3.3)mg/(L·h),半衰期(t1/2)分别为(1.7±0.2)h和(1.6±0.2)h.两制剂的Cmaxtmax,AUC0-10均存在显著性差异.双单侧t检验结果表明,受试制剂Cmax的90%置信区间落在参比制剂的75%～133%范围内,AUC的90%置信区间均落在参比制剂的80%～125%范围内,相对生物利用度为(94.9±14.4)%.结论 两制剂具有生物等效性.     

Bioavailability study of drotaverine from capsule and tablet preparations in healthy volunteers

The bioavailability of drotaverine (CAS 14009-24-6) was investigated after oral administration of a drotaverine capsule preparation (20 mg Droxa mite) and compared to that of a reference tablet preparation. The preparations were investigated in 23 healthy volunteers, aged between 20 and 27 years, according to a randomised two-way, cross-over design in the fasted state. Blood samples for determination of drotaverine plasma concentrations were collected at pre-defined time points up to 30 h following drug administration. A washout period of two weeks separated both treatment periods. Drotaverine plasma concentrations were determined by means of a validated HPLC method (UV detector, imipramine HCl salt as an internal standard). The limit of detection was 6 ng/ml. Values of 1593.92 +/- 949.70 ng x h/l (95% confidence interval (CI): 1183.20-2004.60) for the test and 1705.48 +/- 737.78 ng x h/l (95% CI: 1386.40-2024.50) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum concentrations--Cmax of 121.89 +/- 37.03 ng/ml (95% CI: 104.05-139.80) and 121.85 +/- 37.97 ng/ml (95% CI: 107.09-135.74) and time to reach maximum plasma concentration--Tmax of 1.29 +/- 0.42 h (95% CI: 1.11-1.48) and 1.14 +/- 0.34 h (95% CI: 0.99-1.29) achieved for the test and reference preparations did not differ significantly. The relative bioavailability (AUC(0-infinity) ratio test/reference) and Cmax ratio test/reference were 103.15% (90% CI: 81.68-124.60) and 103.74% (90% CI: 94.10-113.38), respectively. AUC was calculated using two different methods. There were no significant differences between the obtained values. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the European Agency for the Evalution of Medicinal Products (CPMP) and the Food and Drug Administration, it is concluded that the new drotaverine capsule formulation is therapeutically equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.     

Pharmacokinetic profile and bioavailability of a new pharmaceutical formulation of isosorbide-5-mononitrate sustained-release formulation

The pharmacokinetic profile and the bioavailability of a new galenic formulation of isosorbide-5-mononitrate sustained released capsules (Olicard 40 retard) was tested under standardized conditions. 12 healthy, male volunteers (mean age 24.9 +/- 3.0 years) in a randomized, intraindividual crossover design (wash-out phase: 6 days) received the isosorbide-5-mononitrate sustained-release capsules (testformulation) and a standard-release formulation of the same active substance as single dose (40 mg each). Venous blood sampling for analysing the plasma concentration of isosorbide-5-mononitrate was done before and at 21 fixed times after medication. The AUC0----36h of the concentration/time curve was calculated using the linear trapezoidal rule and the AUC0----infinity extrapolated after computing the half-life of the terminal elimination phase. The leading variable was the AUC0----infinity. For the sustained-release preparation an AUC0----36h of 5764.5 +/- 909 ng/ml.h was measured, an AUC0----infinity of 5863.9 +/- 981.9 ng/ml.h was calculated, with a peak maximum (Cmax) of 472.5 +/- 29.7 ng/ml after 2.9 +/- 0.5 h (tmax). For the standard-release formulation an AUC0----36h of 5679.8 +/- 690.3 ng/ml.h was measured, an AUC0----infinity of 5688.7 +/- 695.7 ng/ml.h was calculated, with a peak maximum (Cmax) of 842.4 +/- 100.2 ng/ml after 1.2 +/- 0.2 h (tmax). The bioavailability of the standard-release formulation was postulated to be 100%. The non-parametric calculation of the bioavailability-ratio (geometric Walsh-averages) was 101.47% (95% confidence limits 85.24% to 121.09%). There was no statistically significant difference between the both galenical formulations, the sustained-release preparation has no influence on the total amount of resorption.(ABSTRACT TRUNCATED AT 250 WORDS)