Comparative biological availability of two different ibuprofen granules]

Bioavailability of ibuprofen (CAS 15687-27-1) was investigated in 12 healthy volunteers who received 2 sachets of newly developed effervescent granules (Imbun), each containing 500 mg of ibuprofen lysine salt (corresponding to 292.6 mg of ibuprofen) as the test preparation and 1 sachet of commercially available granules containing 600 mg ibuprofen. Blood samples were withdrawn pre-dose and at 16 occasions until 10 h post dose. Ibuprofen plasma concentrations were assayed by HPLC using a proprietary column-switching technique. Maximum plasma concentrations, Cmax, and times of their occurrence, tmax, were taken from the plasma data directly, areas under the plasma level/time curves, AUC0-10, were calculated using the trapezoidal rule. Pharmacokinetic parameters were checked for significant differences using ANOVA with p = 0.05. When the test preparation was applied maximum ibuprofen levels of 60 +/- 17 micrograms/ml were reached at 27 +/- 17 min p. appl. while Cmax was 52 +/- 12 micrograms/ml at tmax = 94 +/- 27 min after application of the reference preparation. AUC values were 150 +/- 44 microgramsh/ml (test) and 148 +/- 33 microgramsh/ml (reference), respectively. Thus, relative bioavailability of ibuprofen was 101.8 +/- 16.3% (or 104.1 +/- 16.7% when the slight differences in doses were corrected for). Differences in extent of absorption as measured by AUC and Cmax proved to be insignificant whereas differences in absorption rate as measured by tmax were highly significant (p < 0.001).     

Pharmacokinetics and bioequivalence study of a generic amlodipine tablet formulation in healthy male volunteers

Two different tablets containing amlodipine besylate (CAS 111470-99-6) (Vazkor 10 mg tablet as test preparation and 10 mg tablet of the originator product as reference preparation) were investigated in 18 healthy male volunteers in order to compare the bioavailability and prove the bioequivalence between both treatments after oral single dose administration. The study was performed according to an open-label, randomized, two-period cross-over design with a wash-out phase of 21 days. Blood samples for pharmacokinetic profiling were taken up to 144 h post-dose, and amlodipine plasma concentrations were determined with a validated LC-MS/MS method. Maximum plasma concentrations (Cmax) of 6,183.7 pg/ml (test) and 5,366.7 pg/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 267,231.0 pg x h/ml (test) and 266,061.7 ng x h/ml (reference) were calculated. The median tmax was 5.6 h (test) and 6.1 h (reference). Plasma elimination half-lives (t 1/2) were 46.46 h (test) and 45.34 h (reference). Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA); 90% confidence intervals were between 93.20%-107.16% (AUC(0-infinity) and 103.36%-123.13% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.     

Pharmacokinetics and bioequivalence study of ranitidine film tablets in healthy male subjects

The aim of the present study was to compare the bioavailability of ranitidine (CAS 66357-35-5) from two different ranitidine hydrochloride (CAS 66357-59-3) film tablets (Ranitab 150 mg film tablets as test preparation and 150 mg film tablets of the originator product as reference preparation). The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 9 days. Blood samples for pharmacokinetic profiling were taken up to 24 h post-dose, and ranitidine plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 461.8 ng/ml (test) and 450.6 ng/ ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC (0-infinity) of 2,488.6 ng . h/ml (test) and 2,528.8 ng . h/ml (reference) were calculated. The median tmax was 2.83 h (test) and 3.04 h (reference). Plasma elimination half-lives (t1/2) of 2.78 h (test) and 2.89 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 91.93 %-106.98 % (AUC (0-infinity) and 92.34%-118.85% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90 % confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 %-125 %.     

Bioequivalence of different prednisolone tablet formulations

The relative bioavailability of different prednisolone (CAS 50-24-8) tablet formulations (Prednisolon Ferring 2, 5, and 20 mg) was investigated in comparison to a reference formulation. The study was performed in a GCP/ICH-conform manner using a randomized cross-over design in 13 healthy volunteers. With respect to the pharmacokinetic parameters Cmax (maximal prednisolone concentration), AUC0-12 h (area under the concentration-time curve until 12 h after drug intake), AUC0-infinity (area under the concentration-time curve until infinity), and t1/2 (elimination half-life time), 10 x 2 mg prednisolone tablets did not show any relevant differences as compared to the reference (1 x 20 mg) meaning that the 90% confidence intervals were within the given 0.80-1.25 limits for the decision of bioequivalence. Although not statistically significant, tmax (time to reach the maximal prednisolone plasma concentration) was 11 min shorter regarding the test preparation as compared to the reference. The pharmacokinetic parameters of 4 x 5 prednisolone tablets were also well in accordance with the reference. The most important parameters Cmax, AUC and t1/2 were within the defined limits for the acceptance of bioequivalence and, in addition, tmax did not show any significant differences. The 20 mg prednisolone tablet formulation showed almost identical parameters of Cmax, AUC, t1/2 und tmax in comparison to the reference substance. Taken together, the results of the bioavailability parameters indicate the bioequivalence of the three prednisolone test preparations as compared to the reference.     

Bioavailability investigation of two different oral formulations of doxepin

Two different oral doxepin (CAS 1668-195) formulations (Doxepin-ratiopharm 25 mg film-coated tablets as test preparation and 25 mg dragées of the reference preparation) were investigated in 30 healthy male and female volunteers in order to prove bioequivalence between these preparations. A single 75 mg oral dose (3 units of test or reference preparation) was given according to a randomised two-way cross-over design in the fasted state. Blood samples for determination of plasma concentration of doxepin and its metabolite N-desmethyldoxepin were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of three weeks separated both treatment periods. Doxepin and N-desmethyldoxepin plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 193,463 pgh/ml (test preparation) and 197,988 pg h/ml (reference preparation) for doxepin as well as values of 313,298 pg h/ml (test preparation) and 306,663 pgh/ml (reference preparation) for N-desmethyldoxepin for the parameter AUC0-infinity demonstrate a nearly identical extent of drug absorption. Maximum concentrations (Cmax) for doxepin/N-desmethyldoxepin of 15,960.06/6,883.69 pg/ml and 18,614.73/6,846.62 pg/ml were achieved for test and reference preparation. Time to reach doxepin maximum plasma concentration (tmax) was 1.98 h for both preparations and for N-desmethyldoxepin tmax was 4.52 h (test preparation) and 4.15 h (reference preparation). Cmax and AUC0-infinity values were tested for statistically significant differences by means of the Two One-Sided T-Tests procedure following ln-transformation of data. Bioequivalence was assumed if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for ln-transformed AUC0-infinity and 70%-143% for ln-transformed Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.     

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 investigation of two different oral formulations of Tetrazepam

Two different oral tetrazepam (CAS 10379-14-3) formulations (Tetrazepam-ratiopharm film-coated tablets as test preparation and tablets of a reference preparation marketed in France) were investigated in 20 healthy volunteers in order to prove bioequivalence between these preparations. A single 50 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of tetrazepam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A washout period of 14 days separated both treatment periods. Tetrazepam plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 3873.08 ngh/ml (test preparation) and 3930.69 ngh/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 482.08 ng/ml and 465.14 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 1.39 hours for both preparations. Cmax and AUC0-infinity-values were tested parametrically by an analysis of variance (ANOVA). Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for AUC0-infinity and 70%-143% for Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.     

Bioavailability investigation of two different oral formulations of methylprednisolone

Two different oral methylprednisolone (CAS 83-43-2) formulations (Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of a reference preparation (R)) were investigated in 16 healthy volunteers in order to prove bioequivalence between these preparations. A single 8 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of methylprednisolone plasma concentrations were collected at pre-defined time points up to 16 h following drug administration. A washout period of 3 days separated both treatment periods. Methylprednisolone plasma concentrations were determined by means of a validated HPLC method. Values of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity-values were tested parametrically by the two one-sided t-test procedure. Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the results obtained in this study, bioequivalence between Methylprednisolone ratiopharm and the reference preparation was demonstrated.     

The bioequivalence of two nifedipine fluid capsules

Bioequivalence of Two Nifedipine Liquid Capsules Plasma concentration-time profiles of nifedipine were determined in an open, randomised cross-over study on 12 healthy volunteers after application of 10 mg nifedipine as two different soft gelatin capsule preparations. In vitro dissolution tests showed a significant difference between the reference preparation (R) and the generic preparation (P). Maximal nifedipine plasma concentrations (Cmax) measured at tmax (0.6 h, median) for P averaged 87.5 +/- 32.7 micrograms/l, corresponding values for R were 95.4 +/- 41.1 micrograms/l and 0.46 h. Differences in Cmax and tmax values were not statistically significant. Mean areas under the curves AUC(0-10 h) were 128.7 +/- 59.9 micrograms.h/h after p and 123.3 +/- 49.3 micrograms.h/l after R (n.s.). 95% confidence intervals for indices of bioavailability based on AUC and Cmax overlapped, indicating that the two preparations are bioequivalent.     

盐酸左氧氟沙星片在健康人体内的药代动力学和 生物等效性研究

目的:研究已上市盐酸左氧氟沙星片在健康中国人体内的生物等效性。方法:48例健康志愿者随机分组,分别在空腹及进食高脂餐后,两周期双交叉单剂量口服盐酸左氧氟沙星片及其参比制剂左氧氟沙星片各500 mg,采用高效液相色谱-串联质谱法测定给药前与给药后48 h内不同时间点的血药浓度,计算主要药代动力学参数,评价生物等效性。结果:在空腹试验中,盐酸左氧氟沙星片及其参比制剂的AUC0~48 h分别为(50.0±8.4)、(48.8±8.6)μg·h·mL^-1,Cmax分别为(6.15±1.42)、(5.98±1.55)μg·mL^-1,tmax分别为(1.19±0.62)、(1.30±0.73)h,t1/2分别为(6.56±1.13)、(6.51±1.14)h^-1,相对生物利用度为(103.0±8.7)%;在餐后试验中,盐酸左氧氟沙星片及其参比制剂的AUC0~48 h分别为(45.4±8.4)、(44.5±8.2)μg·h·mL^-1,Cmax分别为(5.85±1.08)、(6.58±1.89)μg·mL^-1,tmax分别为(1.93±0.72)、(1.82±0.81)h,t1/2分别为(6.69±0.81)、(6.63±0.76)h^-1,相对生物利用度为(102.3±5.3)%。结论:盐酸左氧氟沙星片与其参比制剂具有生物等效性。     

Comparative bioavailability of 875 mg amoxicillin tablets in healthy human volunteers

OBJECTIVE: To compare the bioavailability of amoxicillin 875 mg tablets (EMS Sigma Pharma used as test formulation) and Amoxil BD 875 mg tablets (GlaxoSmithKline used as reference formulation) in 26 healthy volunteers. MATERIAL AND METHODS: 26 healthy volunteers (13 males and 13 females) received each formulation in an open, 2 x 2 crossover, randomized study with seven days of washout period between doses. Plasma samples were obtained over a 12-hour interval after administration. Plasmatic amoxicillin concentrations were obtained by combined reversed-phase liquid chromatography and mass spectrometry with positive ion electrospray ionization using the select ion monitoring method. AUC was calculated by the trapezoidal rule extrapolation method. Cmax and tmax were compiled from the plasmatic concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC0-inf, AUC0-12 h, Cmax and untransformed tmax. RESULTS: The mean values (+/- SD) for AUC0-12 h (microg x h x ml(-1)), AUC0-inf (microg x h x ml(-1)), Cmax (microg x ml(-1)), t1/2 (h) and tmax (h), were, respectively: 55.42 (+/- 16.85), 55.42 (+/- 16.85), 18.59 (+/- 6.3), 1.49 (+/- 1.57) and 2.04 (+/- 0.75) concerning the test formulation, and 51.11 (+/- 18.9), 51.29 (+/- 19.12), 17.83 (+/- 5.86), 1.52 (+/- 1.31) and 2.02 (+/- 0.87) concerning the reference formulation. Confidence intervals (90%) of amoxicillin means of AUC0-12 h and Cmax ratios (test/reference) were: 0.961-1.149 and 0.914-1.142, respectively, agreeing with the bioequivalence criteria established by the Brazilian National Health Surveillance Agency. CONCLUSION: Both formulations were bioequivalent based on both the rate and extent of absorption.     

Comparative bioavailability study of two ibuprofen preparations after oral administration in healthy volunteers

The bioavailability of a new ibuprofen (2-(p-isobutylphenyl)propionic acid, CAS 15687-27-1) preparation was compared with a reference preparation of the drug in 23 healthy male volunteers, aged between 19 and 27. A single dose of 400 mg was given orally in the fasted state, using a randomized two-way crossover study. A washout period of two weeks separated both treatment periods. Ibuprofen plasma levels were determined by means of a validated HPLC method (UV detector). Values of 154.48 +/- 53.27 microg x h/ml (95 % confidence interval CI: 133.50-177.03) for the test, and 140.86 +/- 44.82 microg x h/ml (95% CI: 122.53-159.16) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum plasma concentrations Cmax of 39.53 +/- 7.11 microg/ml (95 % CI: 35.97-41.78) and 37.71 +/- 8.67 microg/ml (95% CI: 33.37-40.46) achieved for the test and reference preparations did not differ significantly. AUC(0-infinity) and Cmax ratios (90% CI) were within the 80-125% interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new ibuprofen preparation is therapeutically equivalent to the reference preparation for both, the extent and the rate of absorption, after single dose administration in healthy volunteers.     

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 investigation of two different oral formulations of citalopram, a so-called 'second generation' antidepressant drug

Citalopram (CAS 59729-33-8) belongs to the so-called 'second generation' antidepressant drugs and is used for the treatment of patients with major depression or other depressive disorders. In the present study, two different oral citalopram formulations (Citalopram-ratiopharm film-coated tablets as test preparation and tablets of a reference preparation distributed in Germany) were investigated in 20 healthy volunteers in order to prove bioequivalence between both preparations. A single 40 mg oral dose was administered according to an open, randomised, two-period cross-over design in the fasted state. Blood samples for determination of citalopram plasma concentrations were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of 21 days separated both treatment periods. Citalopram plasma concentrations were determined by means of a validated HPLC method with fluorescence detection. Maximum plasma concentrations (Cmax), of 34.77 ng/ml (test) and 34.42 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC0-infinity) of 1,719.69 ng*h/ml (test) and 1,725.71 ng*h/ml (reference) were determined. The results showed nearly identical rate and extent of drug absorption. Also further pharmacokinetic parameters were well comparable with each other. Thus, tmax showed values of 3.29 h (test) and 3.77 h (reference). The plasma elimination half-life (t1/2) was 42.50 h (test) und 44.46 h (reference). Both primary target parameters Cmax and AUC0-infinity were tested parametrically by analysis of variance (ANOVA). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90 % confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80 %-125 %.     

Biologic availability and hemodynamic actions following administration of sublingual glycerol trinitrate. A new delivery system]

Bioavailability and Hemodynamic Properties of Sublingually Applied Glyceryl Trinitrate/A new delivery system Bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) was investigated in 16 healthy subjects after sublingual application of 0.8 mg GTN from either a reference product (B) where GTN release is effected by fluorochlorohydrocarbon (FCH) or a test product (A) (Corangin Nitrospay) where GTN release is effected FCH-independently by a pumping system. Plasma concentrations of GTN and hemodynamic effects (digital plethysmography) were measured until 30 min after application. There was no significant difference (Wilcoxon's matched pairs signed rank test) in AUCo-t (A: 8.9 +/- 7.3 ng x h/ml; B: 8.3 +/- 7.6 ng x h/ml) and Cmax (A: 1.43 +/- 1.26 ng/ml; B: 1.13 +/- 1.06 ng/ml), but tmax was significantly shorter after application of the test product (A: 4.6 +/- 1.0 min; B: 6.7 +/- 2.7 min, p less than 0.01). Nonparametric confidence limits (90%) were 0.80-1.89 for AUCo-t (point estimator of the median 1.14), 0.92-2.78 for Cmax (point estimator 1.06) and 0.61-0.90 for tmax (point estimator 0.75). EC50-values obtained from the individual concentration/effect-curves were linked with the concentration/time-curves to establish the time of reaching EC50 (tEC50). GTN response did not differ for both preparations (EC50A: 0.25 +/- 0.24 ng/ml; EC50 B: 0.34 +/- 0.36 ng/ml), coincident with tmax, tEC50 was significantly shorter after administration of (A) (A: 1.8 +/- 0.3 min, B: 2.7 +/- 1.0 min). With respect to the variability of GTN pharmacokinetics, the test preparation shows superior bioavailability and a faster onset of hemodynamic action.     

Pharmacokinetics and absolute bioavailability of ibuprofen after oral administration of ibuprofen lysine in man

The lysine salt of d,l-2-(4-isobutylphenyl)-propionic acid (ibuprofen lysine) was administered as a single oral dose of 500 mg by means of commercially available coated tablets (Imbun).* To assess the absolute bioavailability of ibuprofen after its oral application as a lysine salt, intravenous injections of ibuprofen solutions containing 200 mg and 400 mg of the drug served as reference application. In a partially randomized cross-over design, 8 healthy male volunteers received three different single dose administrations which were separated by wash-out periods of 4 days each. Ibuprofen plasma concentrations were determined by HPLC using direct injection, pre-column enrichment and column switching techniques. From the results of intravenous injections one can deduce linear ibuprofen pharmacokinetics within the considered dosage range, with corresponding AUC0-infinity values of 3786 micrograms * min ml-1 and 7260 micrograms * min ml-1 for the 200 mg and 400 mg doses, respectively. The values of plasma clearances as well as those of different volumes of distribution showed remarkable constancy after evaluation from both intravenous injections. The absorption of orally administered ibuprofen lysine proved to be rapid, resulting in a mean peak plasma level (Cmax) of 31 micrograms ml-1 ibuprofen and in a mean time to peak (tmax) of 45 min. The absolute bioavailability of ibuprofen amounts to 102.7 per cent, indicating a complete absorption of ibuprofen when administered as its lysine salt. Drug tolerability was excellent for the oral administration of ibuprofen lysine as well as for the intravenous treatments with ibuprofen free acid. Only mild and transient adverse drug reactions such as mild burning or dragging sensation during injection or mild redness at the site of injection were reported.     

Comparative bioavailability of clarithromycin formulations in healthy brazilian volunteers

OBJECTIVE: To compare the bioavailability of clarithromycin 500 mg tablets (Merck S.A Industrias Quimicas, Sao Paulo, SP, Brazil, used as test formulation) and Klaricid (Abbott Laboratórios do Brasil Ltda, Sao Paulo, SP, Brazil, used as reference formulation) in 24 healthy volunteers. MATERIAL AND METHODS: The study was conducted using an open, randomized, two-period crossover design with one-week interval between doses. Blood samples were collected at pre-dose, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours after the administration. AUC was calculated by the trapezoidal rule extrapolation method. Cmax and tmax were compiled from the plasmatic concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(0-inf), AUC(0-24 h), Cmax and untransformed tmax. RESULTS: Intraindividual coefficient of variation (CV%) values were 14.25% and 12.62%, respectively for Cmax and AUC(0-24 h). The geometric mean values (+/- SD) for AUC(0-24 h) (microg x h/ml), AUC(0-inf) (microg x h/ml), and Cmax (microg/ml) for test medication were 18.56 (+/- 6.87), 18.8 (+/- 5.70) and 2.45 (+/- 0.88); the obtained values for reference medication were 18.29 (+/- 5.39), 19.10 (+/- 7.21) and 2.5 (+/- 0.69). 90% Cl for clarithromycin geometric mean of AUC(0-24 h), AUC(0-inf) and Cmax ratios (test/reference) were: 93.6-105.9%, 93.8-106.2% and 89- 103.2%. CCONCLUSION The test medication was considered bioequivalent to the reference medication based on the rate and extent of absorption.     

头孢地尼分散片的人体生物等效性研究

目的:研究头孢地尼分散片在健康人体中的药动学和生物等效性。方法:采用微生物法测定20名健康志愿者单剂量交叉口服400mg头孢地尼分散片(受试制剂)和头孢地尼胶囊(参比制剂)后不同时间血清中的药物浓度。结果:受试制剂与参比制剂药-时曲线均符合一房室开放模型,tmax分别为(3.48±0.53)、(3.60±0.48)h,Cmax分别为(2.10±0.32)、(2.15±0.26)mg·L-1;t1/2ke分别为(2.41±0.39)、(2.33±0.41)h,AUC0~12分别为(9.51±1.65)、(10.05±1.72)mg·h·L-1,AUC0~∞分别为(10.43±1.62)、(11.01±1.81)mg·h·L-1。受试制剂相对于参比制剂的生物利用度为(96.03±14.89)%。结论:两种制剂具有生物等效性。     

Relative bioavailability of fluoride from monofluorophosphate tablets after single oral administration

The study was conducted on 12 healthy male Caucasian volunteers of an average age of 27.8 +/- 4.0 years with single oral doses of the following products: 1. sodium monofluorophosphate tablets (MFP-tablets, Mono-Tridin); 2. aqueous solution of 23.2 mg of sodium fluoride (NaF solution-reference); 3. aqueous solution of sodium monofluorophosphate (MFP solution). The three products were equivalent in fluorine content with 10.5 mg F. The bioavailability was evaluated on the basis of the plasma levels and of the urinary excretion of fluoride. The study was designed as a triple latin-square crossover and each subject received the three products in three different periods, at empty stomach. After administration of the products, fluoride appeared quickly in blood (lag time between 0.07 and 0.13 h) and invaded rapidly the blood (invasion t1/2 from 0.04 to 0.15 h). The Cmax of fluoride in plasma was 439 ng/ml at tmax of 1.08 h after MFP tablets, 430 ng/ml at a tmax of 0.51 h after NaF solution and 403 ng/ml at tmax of 0.62 h after MFP solution. The differences for the Cmax were not statistically significant. The relative bioavailability of fluoride from MFP tablets, estimated from the AUC, was 1.35, and significantly larger than that from the reference NaF solution. Fluoride was eliminated from plasma with an initial fast rate (t1/2 from 0.68 to 1.03 h) and a terminal slower rate (t1/2 from 4.71 to 7.37 h). The plasma levels of fluoride were consistent with a two-compartment open pharmacokinetic model after extravascular administration. In the 24 h following the administration the urinary excretion of fluoride accounted for 50-53% of the administered dose, without significant difference between the three products. The three products were well tolerated and no systemic or gastric adverse reaction was recorded.     

Pharmacokinetics and bioequivalence study of doxycycline capsules in healthy male subjects

The aim of the present study was to compare the bioavailability of doxycycline (CAS 564-25-0) from two different doxycycline hyclate (CAS 24390-14-5) capsules (Monodoks 100 mg capsule as test preparation and 100 mg capsule of the originator product as reference preparation) in 24 healthy male subjects. The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 16 days. Blood samples for pharmacokinetic profiling were taken up to 72 h post-dose, and doxycycline plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 1,715.1 ng/ml (test) and 1,613.3 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 28,586.5 ng x h/ml (test) and 29,047.5 ng x h/ml (reference) were calculated. The median tmax was 1.88 h (test) and 2.00 h (reference). Plasma elimination half-lives (t1/2) of 16.49 h (test) and 16.75 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 92.39 %-103.53% (AUC(0-infinity)) and 98.45%-111.74% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 0%-125%.