Biopharmaceutical comparison of two levothyroxine sodium products

The relative bioavailability and therapeutic equivalence of two brands of levothyroxine sodium tablets, Levothroid and Synthroid, were compared in patients who had been receiving long-term levothyroxine replacement therapy. Eighteen patients with primary hypothyroidism were randomly assigned to receive therapeutic dosages of Levothroid or Synthroid for 43 days and then were switched to the opposite product for 43 more days. The pharmacokinetic profiles of the two drugs were evaluated on days 43 and 86 by analyzing blood samples drawn at various intervals after the final dose. Relative bioavailability was determined by comparing the absorption profiles and areas under the serum concentration-time curves (AUCs) of total and free serum thyroxine. In addition, the potency of the levothyroxine sodium tablets was determined by high-performance liquid chromatography. The time to reach maximum concentration and the maximum concentration of total thyroxine after treatment with Levothroid did not differ significantly from those after treatment with Synthroid. The mean +/- S.D. AUC of total thyroxine after Levothroid administration (2339 +/- 404 pg.hr/mL) was slightly but significantly higher (p = 0.047) than that following Synthroid (2169 +/- 422 pg.hr/mL). However, the main index of biological activity, thyrotropin concentration, did not differ significantly between the two products. All tablets tested were within the stated potency requirements of the USP. The AUC of total serum thyroxine and the serum thyrotropin concentration after long-term replacement therapy with Levothroid or Synthroid indicate that any differences in bioavailability between the two products are clinically unimportant and that the two products are therapeutically interchangeable.     

A study in normal human volunteers to compare the rate and extent of levothyroxine absorption from Synthroid and Levoxine.

Numerous branded and generic formulations of levothyroxine (LT4) sodium tablets are currently available. Results from previous studies attempting to examine the comparative bioavailability of these formulations are difficult to interpret because of subject heterogeneity, single time-point blood sampling, varying degrees of hypothyroidism, and other factors. This study was devised to compare the rate and extent of absorption of LT4 from different LT4 sodium tablet formulations, in a simple model using a single-dose two-way single-blind, randomized cross-over design in 30 normal, healthy, nonpregnant, female subjects. This design controlled for many factors that limited previous LT4 bioavailability studies. Subjects were given a single 600 micrograms dose of LT4 as either Synthroid (Boots Pharmaceuticals, Inc., Lincolnshire, IL) tablets (formulation A) or Levoxine tablets (Daniels Pharmaceuticals, St. Petersburg, FL; formulation B). Measurements of baseline-corrected total T4 serum concentrations determined at multiple time points demonstrated statistically significant differences between the two formulations at the 1.00, 3.00, 5.00, and 18.00 hour sampling times. Statistically significant differences for area under the curve (AUC) (0 to 48 hours) (formulation A, 159.9 +/- 9.4 micrograms-hour/dL; formulation B, 193.4 +/- 10.1 micrograms-hour/dL) and maximum peak plasma concentration (Cmax) (formulation A, 5.91 +/- .34; formulation B, 7.12 +/- .32) also were demonstrated. Furthermore, the ratio of the baseline-corrected total T4 concentrations (B/A x 100) were 120.9% for AUC and 120.5% for Cmax. These data demonstrate that the administration of Synthroid and Levoxine result in a significantly different rate and extent of absorption of LT4, and therefore these two formulations cannot be considered bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple level C in vitro/in vivo correlation of dissolution profiles of two thyroxine tablets with pharmacokinetics data obtained from patients treated for hypothyroidism

In a previous study aimed to compare the bioavailability of two levothyroxine tablets, we found a good relation between their pharmacokinetics parameters and dissolution profiles, employing the USP dissolution conditions in use at that time (24th edition). Despite the formulations were considered bioequivalent, the test product presented values of AUC and concentrations at steady-state significantly lower (about 10%) than the reference ones. The purpose of the present study was to evaluate if the actual pharmacopeial conditions (with alterations introduced in the first supplement of USP 24) would also allow a good correlation between bioavailability and dissolution data. The partial AUCs were correlated with cumulative levothyroxine amount dissolved at three different times, for each dissolution condition. Employing the old method, test tablets had a slower dissolution rate than the reference ones, resulting in a quite good multiple level C in vitro/in vivo (IVIV) correlation. On the other hand, the very fast dissolution profiles obtained in the actual condition lead to a worse IVIV correlation. Present work indicates that the mild conditions proposed in the older US Pharmacopeia were better than the actual in order to discriminate dissolution profiles of levothyroxine tablets which present subtle, but significant, differences in their pattern of absorption.     

Bioequivalence study of levothyroxine tablets compared to reference tablets and an oral solution

The study was designed to evaluate the bioequivalence of three levothyroxine sodium (CAS 51-48-9) formulations, i.e. a test and a reference tablet and an oral solution. A bioequivalence study was carried out in 25 healthy volunteers, who were administered a single dose of 600 microg levothyroxine in the form of the test formulation (levothyroxine sodium tablets 200 microg; Eferox), the originator product, and an oral solution. The trial was performed in one study center according to an open, randomized, three-way cross-over design with wash-out periods of 35 days between administration. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of levothyroxine and triiodothyronine were determined by radioimmunoassay with I125 labeling method. The levothyroxine mean Cmax were 112.0+/-17.3 ng/ml, 113.4+/-18.5 ng/ ml and 111.3+/-15.1 ng/ml, while the mean AUC0-24 were 2263.7+/-332.8 ng x h/ ml, 2307.3+/-351.3 ng x h/ml and 2286.1+/-331.0 ng x h/ml for the test and reference tablets as well as for the oral solution, respectively. No significant differences were found of principal pharmacokinetic parameters between the studied formulations. The 90%-confidence interval for the primary target parameters, intra-individual ratios of AUC0-24 and Cmax of levothyroxine were within the acceptance ranges for bioequivalence trials, i.e. AUC0-24 0.954-1.016 and 0.966-1.011 as well as Cmax 0.948-1.027 and 0.968-1.032 for test tablets versus reference tablets and the oral solution, respectively. Similar results were observed for triiodothyronine. In the light of the present study it can be concluded that the levothyroxine test tablet is bioequivalent to the reference formulation in respect of extent and rate of absorption. The results of the present trial confirm the findings of a previous study, performed under steady-state conditions with Eferox tablets 100 microg in patients without thyroid function.     

Use of rabbits for GI drug absorption studies: relationship between dissolution rate and bioavailability of griseofulvin tablets

The correlation between the dissolution rate and bioavailability of griseofulvin tablets was studied in stomach-emptying-controlled rabbits and in humans. Three different test tablets, each consisting of two dose levels (62.5 or 125 mg) of griseofulvin, were used. The dissolution rates in 0.5 hr were approximately 75, 40, and 12%. With oral administration at 62.5 mg/rabbit, the ratio of peak plasma level, Cmax, was 1.00:0.66:0.40 and that of the area under the curve (AUC) was 1.00:0.73:0.46 for the three tablets. The corresponding C'max ratio was 1.00:0.74:0.34 and the AUC ratio was 1.00:0.72:0.33 in humans at the dose level of 500 mg. A good correlation was observed for the rank order of Cmax and AUC between rabbits and humans, but such a correlation was not seen between in vivo data and in vitro data at a larger dose of 125 mg/rabbit. This finding was attributable to the dose, which exceeded the GI drug dissolution or absorption capacities. These results suggest that the stomach-emptying-controlled rabbit is useful for evaluating oral dosage forms for human use and that dose level selection is important in the bioavailability study of a barely water-soluble drug.     

氯氮平胃内漂浮片兔体内药物动力学和体内外相关性

为了比较氯氮平漂浮片 (自制 )和普通片兔体内药物动力学、相对生物利用度及体内外相关性。用 4只新西兰大白兔自身交叉对照、单剂量灌胃氯氮平漂浮片或普通片各 5 0mg ,采用HPLC法测定血浆氯氮平浓度 ,3p97程序拟合血药浓度 时间数据。结果表明氯氮平漂浮片和普通片符合单室模型特征 ,求得药物动力学参数 :tmax分别为 (3 0 5 7± 0 0 5 9)和 (1 188± 0 191)h ;Cmax分别为 (8 795± 0 494)和 (11 182± 3 45 7) μg/mL ;AUC( 0～t) 分别为 (6 6 0 15± 7 0 2 6 )和 (5 4 881±1 180 ) μg/mL·h ;漂浮片相对生物利用度为 (12 0 2 88± 6 2 77) % ;其体内吸收与体外释药有良好的相关性 (r =0 9811)。     

左甲状腺素钠2种配方片剂人体生物利用度比较

目的:评价进口新配方与旧配方左甲状腺素钠片剂的人体相对生物利用度及生物等效性。方法:24名健康男性受试者,随机分为2组,分别于早晨空腹单剂量口服新配方或旧配方左甲状腺素钠片600μg。35d清洗期后再交叉给药。分别在服药前30,15,4min内和服药后0.5,1.0,1.5,2.0,2.53.0,3.5,4.0,6.0,8.0,10.0,12.0,18.0,24.048.0h取静脉血,用放射免疫分析法测定血清样品T4和T3的浓度。结果:受试者口服新配方和旧配方左甲状腺素钠片剂后血清中T4呈明显时量变化主要药动学参数如下:tmax为(3.4±s2.3)和(3.5±2.1)h,cmax为(168±39)和(160±34)μg·L-1AUC0～48为(5640±1060)和(5620±1010)μg··L-1。而血清中T3无明显时量变化。结论:新配方和旧配方左甲状腺素钠片剂相对生物利用度为(102±18)%,2种配方的制剂具有生物等效性。     

In vitro and in vivo characteristics of some commercial phenobarbital tablets

Using an incompletely randomized crossover study design, the oral bioavailability characteristics of 7 different brands of phenobarbital tablets, USP, 100 mg was investigated in 5 adult, male volunteers. From plasma drug concentration-time data, best estimates for the bioavailability parameters of peak plasma phenobarbital concentration (Cmax) and time to peak concentration (tmax) were obtained by curve fitting and area under the plasma drug concentration-time curve (AUC) computed with the trapezoid rule. No significant difference in Cmax or normalized AUC was seen for the 7 products investigated. Additionally, a difference in tmax was observed between 2 preparations (A and E) only (p less than or equal to 0.05). All drug products met USP requirements for weight variation and tablet disintegration and all but one product (D) exhibited reasonably good and similar dissolution characteristics in simulated gastric fluid. No correlation between various in vitro dissolution parameters and in vivo bioavailability of phenobarbital could be found for the 7 phenobarbital products studied.     

Comparative bioavailability of two flurbiprofen products: stereospecific versus conventional approach

In this randomized, crossover study comparing the bioavailability of a film-coated (Ansaid) with a sugar-coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 healthy young men, no significant differences were found for Cmax, tmax or AUC, using a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30-min post-dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7.8 per cent) but significant difference in AUC of the active S-configuration (Froben greater than Ansaid). No significant differences between Ansaid and Froben were found for tmax or Cmax for the S-flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products.     

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.     

Development of a dissolution medium for nimodipine tablets based on bioavailability evaluation.

A marked difference in the dissolution rate between two brands of nimodipine tablets was observed using a newly developed dissolution medium of pH 4.5 acetate buffer containing 0.05% sodium dodecyl sulfate (SDS). However, when pH 4.5 acetate buffer containing 0.3% SDS was used as dissolution medium, which was specified in the edition, the dissolution results of the both brands conformed to the BP requirements and no significant difference in dissolution was observed. The dissolution data obtained for two commercial brands of nimodipine tablets indicate the superiority of the proposed system as a discriminatory dissolution medium for nimodipine tablets. The relative bioavailability of the two brands of nimodipine tablets was determined in healthy adult volunteers after a single dose in a randomized crossover study. Plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry method. Statistical comparison of the AUC(0-T), AUC(0- infinity), C(max), and T(max) indicated a significant difference in the two brands of nimodipine tablets.     

Comparative in vitro dissolution and in vivo bioequivalence of two diclofenac enteric coated formulations

The aim of this study was the comparison of in vitro dissolution and in vivo bioavailability of two different brands of diclofenac sodium (CAS 15307-86-5) enteric coated tablets in healthy male Iranian volunteers in a single-dose, randomized, open-label, single blind study, which was conducted according to a crossover design in healthy volunteers. A washout interval of two weeks was selected between administrations to each subject in this study. Serial venous blood samples over 10 h after each administration to measure diclofenac sodium concentration in serum were obtained, and placed into tubes containing sodium heparin. Then the plasma was separated and kept frozen at -20 degrees C for subsequent analysis with a modified HPLC method with UV detection. In addition, the in vitro dissolution study was performed on the brands. For the test and reference formulation, mean Cmax values were 2257.3 (ng/ml) and 2156 (ng/ml), respectively. The mean AUC(0)tau and AUC(0)infinity were 5726.1 (ng x h/ml) and 5917.8 (ng x h/ml) for the test and 5689.9 (ng x h/ml) and 5967.4 (ng x h/ml) for the reference formulation, respectively. Results show that the 90% confidence intervals for the ratio of test and reference products in Cmax (101.4-114.9%), AUC(0)tau (96.3-109.1%) and AUC(0)infinity (94.7-107.3%) were all within the 80-125% interval proposed by the FDA and EMA. Both formulations released > 80% of drug within 30 min in buffer pH = 6.8 medium. Therefore the diclofenac sodium enteric coated tablets of the test and reference formulations are bioequivalent in terms of rate and extent of absorption.     

泮托拉唑钠肠溶片在中国男性健康志愿者体内的药动学和相对生物利用度研究

目的:研究泮托拉唑钠肠溶试验片与参比片的药代动力学与相对生物利用度。方法:20名男性健康志愿者单剂量口服泮托拉唑钠试验和参比制剂各40mg;采用反相高效液相色谱法测定其血药浓度。用DAS软件计算药代动力学参数,考察其生物等效性。结果:泮托拉唑钠肠溶片在人体的药动学行为符合二房室开放模型,试验片与参比片的主要药代动力学参数:Tmax分别为(3.18±0.54)和(3.30±0.47)h;Cmax分别为(2.98±0.83)和(2.91±0.87)mg·L-1;T12分别为(1.86±0.41)和(1.72±0.48)h;AUC0-t分别为(9.51±3.71)和(9.77±4.55)mg·h·L-1;相对生物利用度为(102.3±19.6)%。结论:泮托拉唑钠肠溶片两种制剂具有生物等效性。     

Investigation of the relationship between in vitro and in vivo release behaviors of acamprosate from enteric-coated tablets

Acamprosate calcium is a highly soluble drug with low permeability that is used to maintain abstinence in alcohol-dependent patients. The aim of this study was to investigate the relationship between in vitro and in vivo behaviors of acamprosate from enteric-coated tablets. The in vitro release behavior of acamprosate tablets in pH 6.8 buffer solution was determined in three dissolution conditions, 50 and 150 rpm (paddle method) and 180 rpm (basket method). The results of this in vitro experiment indicated that acamprosate tablets hardly disintegrated, and drug dissolution was retarded despite the extremely hydrophilic nature of the drug. A single dose (333 mgx2 tablets) of each formulation was orally administered to four beagle dogs under fasting conditions, and the pharmacokinetic parameters were calculated. The mean AUC0-48, Cmax, Tlag and Tmax for the two types of tablets ranged from 41.5-53.6 microg.h/mL, 4.3-4.5 microg/mL, 2.0-2.5 h and 3.8-4.0 h, respectively. In conclusion, it is suggested that retarded drug release from the tablets and the low drug permeability may result in poor absorption and erratic bioavailability of this drug in humans.     

Bioavailability studies of theophylline ethylcellulose microcapsules prepared by using ethylene-vinyl acetate copolymer as a coacervation-inducing agent

The bioavailability of theophylline microcapsules prepared by using ethylene-vinyl acetate (EVA) copolymer as a coacervation-inducing agent was studied in rats. The dissolution rate of the microcapsules was determined by the rotating-basket and rotating-bottle methods. The higher the concentration of EVA copolymer used, the more sustained was the release of theophylline from the microcapsules. The mean maximum serum levels (Cmax) and time to maximum serum levels (tmax) were not significantly different for theophylline microcapsules prepared by a lower concentration of EVA copolymer (0 and 0.83%, respectively), compared with those for theophylline powder; whereas a significant difference was found when the higher concentration of EVA copolymer was used (greater than 1.7%). With regards to the area-under-the-curve (AUC) value, there was no significant difference between the theophylline powder and theophylline microcapsules. The elimination kinetics and the corresponding half-life (t1/2) were significantly different when the concentration of EVA copolymer was greater than 3.3%. From the above results, it is evident that theophylline microcapsules prepared by using 3.3 and 5.0% EVA copolymer as the coacervation-inducing agent may act as sustained-release dosage forms. The correlation between the dissolution rate in vitro and the bioavailability in rats for theophylline microcapsules was investigated. The mean Cmax and tmax correlated well with the time taken to release 75% of the drug in vitro (t 75%); however, the mean AUC showed no valid correlation with t 75%. This implies that the dissolution rate correlated better with the rate of absorption (Cmax, tmax) than with the extent of absorption (AUC).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of digoxin tablets in healthy volunteers

The bioavailability of digoxin generic tablets manufactured in Korea (formulations A & B) were compared to a standard (formulation C; Lanoxin brand digoxin, Burroughs Wellcome, USA) in 12 healthy Korean male volunteers (mean age 31.4 years) in a single dose, randomized, complete block crossover study. Using a Latin square design, each of the subjects was randomized to the order number and allocated to each of the three treatments of 0.5 mg oral digoxin. Digoxin concentrations in serum and urine samples collected for 48 hours after dosing were measured by fluorescence polarization immunoassay and radioimmunoassay, respectively. Treatments were compared by using nonlinear least squares regression analysis to evaluate the following pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (Tmax); area under the serum concentration-time curve for 0-12 hours (AUC0-12); and cummulative urinary excretion for 0-48 hours (CUE0-48). Mean AUC0-12, Cmax, and CUE0-48 values for formulations B and C were significantly different from formulation A (p < 0.001), but not significantly different from each other. Based on AUC0-12 and CUE0-48, respectively, the relative availability of formulation B was 87.5% and 89.6% and the relative availability of formulation A was 43% and 35% when compared to formulation C (the standard).     

Pharmacokinetics and bioavailability of acyclovir sustained-release tablets in dogs.

The pharmacokinetics and bioavailability of acyclovir sustained-release tablets in dogs were investigated. Blood concentrations of acyclovir were determined by RP-HPLC after a single oral dose of two kinds of acyclovir tablets given separately to 6 beagle dogs. The main pharmacokinetics parameters of the acyclovir sustained-release tablet were as follows: T1/2, Tmax and Cmax were 4.10 +/- 0.20 h, 4.05 +/- 0.54 h and 6.90 +/- 0.68 [microg x ml(-1), respectively. MRT was 9.02 +/- 0.44 h. Using acyclovir standard tablet as control, relative bioavailability of the acyclovir sustained-release tablet was 152.2 +/- 49.90%. According to the two-tailed t-test, there was a distinct difference in the data for Tmax, Cmax and AUC between acyclovir sustained-release tablets and acyclovir standard tablets, and the absorbability of acyclovir sustained-release tablets was much better than that of the acyclovir standard tablets.     

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.     

国产与进口美洛昔康片单次给药后人体药动学(英文)

目的 :比较健康志愿者国产与进口美洛昔康片的人体药动学和相对生物利用度。方法 :采用单次给药 2周期交叉设计 ,HPLC法测定 12名健康男性志愿者口服 15mg美洛昔康后血药浓度 ,计算药动学参数和国产片的相对生物利用度。结果 :2种制剂的药时曲线符合一级吸收的一室开放模型。国产与进口片的药动学参数分别是AUC0 - 96 为 (6 7±s 14 )mg·h·L- 1和 (6 4± 15 )mg·h·L- 1;AUC0 -∞ 为 (73± 19)mg·h·L- 1和 (70± 18)mg·h·L- 1;Cmax为 (2 .3± 0 .5 )mg·L- 1和 (1.6± 0 .3)mg·L- 1;Tmax为 (2 .0± 1.6 )h和 (6± 3)h ;T12 ke为 (2 5± 6 )h和 (2 4± 5 )h ;MRT为 (4 0± 13)hand (39±8)h。方差分析表明两者AUC之间无显著差异 (P>0 .0 5 ) ,但两者的Cmax和Tmax之间有显著差异 (P<0 .0 5 )。结论 :国产片的释药速率比进口片快 ,其相对生物利用度为 (10 5± 13) %。     

多潘立酮片的人体药代动力学和生物等效性研究

建立了HPLC-FLD法测定人体血浆中多潘立酮的浓度.受试者单剂量口服受试片及参比片后,Cmax分别为(24.60±11.60)和(26.82±10.94)ng?mL-1,tmax分别为(0.7±0.4)和(0.7±0.5)h,AUC0～∞分别为(107.2±49.09)和(106.52±44.67)ng/(h?mL).受试片的相对生物利用度为(105.0±32.4)%,两制剂生物等效.