Comparative bioavailability study of zidovudine administered as two different tablet formulations in healthy adult subjects

AIM: Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. VOLUNTEERS AND METHODS: A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. RESULTS: Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), mean area under the curve from time 0 to infinity (AUC(0-infinity)) and peak plasma concentrations (C(max)) of zidovudine for the generic tablet formulation (2,220.6 ng x h/ml, 2,236.0 ng x h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng x h/ml, 2,158.6 ng x h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC(0-t) AUC(0-infinity) and C(max) between the 2 formulations were within 80-125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 1/h/kg and 2.16 1/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. CONCLUSION: Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.     

Relative bioavailability of rimantadine HCl tablet and syrup formulations in healthy subjects

Twenty healthy male subjects completed an open-label randomized crossover design to assess the bioavailability of 100 mg of rimantadine HCl in tablet and syrup forms relative to an oral solution. Blood samples were drawn and rimantadine plasma concentrations were determined by a GC-MS method. The maximum plasma concentration (Cmax), the time to Cmax (tmax), the area under the plasma concentration-time curve (AUC), and k were compared among treatments using an analysis of variance and the Hauck-Anderson test for bioequivalence. The Hauck-Anderson test was satisfied when the syrup and solution were compared. The relative bioavailability of the syrup was 96%. Both Cmax and AUC were significantly (p less than 0.05) increased (23 and 17%, respectively) when the tablet was compared with the solution. The relative bioavailability of the tablet was 117%. This outcome was unusual and could not be explained. However, this was not anticipated to be of clinical consequence since the majority of the safety and efficacy of rimantadine HCl was established using a tablet.     

Comparative bioavailability study with two amiodarone tablet formulations administered with and without food in healthy subjects

OBJECTIVE: The aim was to assess the comparative bioavailability of two formulations (200 mg tablet) of amiodarone (CAS 19774-82-4) in healthy volunteers of both sexes, with and without food. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 3-week washout interval, in two groups, with and without food. Plasma samples were obtained for up to 240 h post dose. Plasma amiodarone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). From the amiodarone plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained, with and without food: AUC(last), AUC(inf), AUC(0-240h), AUC(0-72h) and C(max). RESULTS: The limit of quantification was 1 ng/mL for plasma amiodarone analysis. The geometric mean and 90% confidence interval CI of Test/Reference percent ratios were, without and with food, respectively: 107.61 (92.73-124.89) and 100.6 (94.1-107.5) for C(max), 107.05 (95.88-119.51) and 100.2 (96.0-104.7) for AUC(last), 107.27 (95.78-120.15) and 100.8 (97.0-104.8) for AUC(0-72h), 106.76 (95.84-118.94) and 100.2 (96.0-104.7) for AUC(0-240h) and AUC(inf) 105.15 (94.18-117.41) and 100.7 (96.6-105.0). CONCLUSION: Since the 90% CI for AUC(0-72) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that the amiodarone 200 mg tablet (test formulation) with and without food was bioequivalent to the reference 200 mg tablet for both the rate and extent of absorption.     

Relative bioavailability study of two nifedipine tablet formulations in healthy male volunteers

OBJECTIVE: To assess the bioequivalence of two oral formulations containing 10 mg of nifedipine. The test preparation were Macorel tablets, the reference preparation were Adalat tablets. SUBJECTS, MATERIAL AND METHODS: The study was designed as a single-dose, three-period crossover randomized design to 18 non-smoker, healthy male volunteers under fasting conditions. Seventeen volunteers completed the study. Plasma samples were analyzed for nifedipine by HPLC after solid-phase extraction. The pharmacokinetic parameters used to assess the bioequivalence of the two formulations were AUC(0-infinite) and AUC(0-t) for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical comparisons of AUC(0-infinite) AUC(0-t), and Cmax data were evaluated after logarithmic transformation by two-way analysis of variance (ANOVA), and differences of Tmax were tested non-parametricaly. RESULTS: Point estimates (90% confidence intervals) of the test/reference ratios were 97.4% (87.6%-108.3%) for AUC(0-infinite) 97.0% (85.6%-110.1%) for AUC0-t, and 107.7% (89.1%-130.7%) for Cmax. No statistically significant difference was found for Tmax and elimination half-life values. CONCLUSION: Therefore, in accordance with the European Union bioequivalence requirements, the test and reference nifedipine preparations are bioequivalent for both the extent and the rate of absorption.     

Comparative bioavailability study with two pantoprazole delayed-released tablet formulations administered with and without food in healthy subjects

OBJECTIVE: To assess the comparative bioavailability of two formulations (40 mg delayed-released [DR] tablet; test and reference) of pantoprazole (CAS 102625-70-7) in healthy volunteers of both sexes, with and without food. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval, in two groups, with and without food. Plasma samples were obtained for up to 24 h post dose. Plasma pantoprazole concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). From the pantoprazole plasma concentration vs. time curves, the pharmacokinetic parameters AUC(last) and C(max) were obtained, with and without food. RESULTS: The limit of quantification was 5 ng/mL for plasma pantoprazole analysis. The geometric mean and 90% confidence interval CI of test/reference percent ratios were, without and with food, respectively: 104.6540% (90.8616%-120.5401%) and 99.9708% (90.9987%-109.8275%) for C(max), 95.6634% (85.2675%-107.3267%) and 89.3500% (83.6630%-95.4237%) for AUC(last). CONCLUSION: Since the 90% CI for AUC(last) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that pantoprazole 40 mg DR tablet (test formulation) with and without food was bioequivalent to the reference 40 mg DR tablet for both the rate and extent of absorption.     

西洛他唑片的人体相对生物利用度

目的　研究2种西洛他唑片在正常人体内的药代动力学与相对生物利用度。方法　用HPLC法测定24名志愿者随机交叉口服2种国产西洛他唑100mg后的血药浓度,用3P97软件计算2药的药代动力学参数与相对生物利度。结果　试验与参比药物的体内药-时曲线呈二室摸型。tmax分别为(3.25±0.99) 和(3.88±1.19) h;Cmax分别为(1.02±0.41)和(0.99±0.37) mg.mL-1;AUC(0-T)分别为(12.65±3.83) 和(12.84±4.10) mg.h.mL-1;t1/2β分别为(19.50±13.72) 和(17.40±11.58) h。经配对t检验,2药药代动力学参数无显著性差异(P>0.05)。西洛他唑片相对生物利用度为 (98.52±13.52)%。结论　2种国产西洛他唑片具有生物等效性。     

Bioequivalence assessment of two different tablet formulations of diltiazem after single and repeated doses in healthy subjects

The study was performed on 14 healthy volunteers in order to compare the pharmacokinetics and hence assess the bioequivalence of two different tablet formulations of diltiazem administered orally. The study was carried out after single doses (60 mg) and repeated doses (60 mg three times a day for six days and 60 mg on the seventh day) according to a randomised, cross-over, open design. The pharmacokinetic parameters AUC0-infinity (ng h/ml), Tmax(h) and Cmax (ng/ml) were calculated for the two formulations after a single dose, while AUCt1-t2 (= AUC for a repetitive dose interval or dosing cycle, ng h/ml) and PTF (peak trough fluctuation) were calculated after repeated doses. The bioequivalence assessment was the shortest 90% confidence interval for the ratio (difference) of expected medians in the respective bioequivalence range (0.80-1.20). The results of this study show that, after either a single dose or repeated doses of test or reference formulations of diltiazem, the pharmacokinetics of the two formulations are similar. The ratios of AUC on day 1 (for single-dose treatment) and on day 7 (for repeated-dose treatment), and the corresponding 90% confidence intervals demonstrate bioequivalence between the two formulations of diltiazem within the accepted range of 0.80-1.20 (80-120%).     

Comparative bioavailability of two cetirizine tablet formulations in Indonesian healthy volunteers

AIM: To compare the bioavailability of two cetirizine tablet (10 mg) formulations (ZyrtecA from UCB Pharma, Spain as a reference formulation and RyvelA from Novell Pharmaceutical Laboratories, Indonesia as a test formulation). MATERIAL AND METHODS: The study was conducted according to an open, randomized, two-period crossover design with a 1-week washout period. Eighteen volunteers participated and all completed the study successfully. Blood samples were obtained prior to dosing and at 0.25, 0.5, 1, 2, 3, 5, 8, 12, 24 and 30 hours after drug administration. Plasma concentrations of cetirizine were monitored using high-performance liquid chromatography over a period of 30 hours after administration. The pharmacokinetics parameter AUC(0-30h), AUC(0-infinity) and C(max) were tested for bioequivalence after log-transformation of data and ratios of t(max) were evaluated non-parametrically. RESULT: The point estimates and 90% confidence intervals for AUC(0-30h), AUC(0-infinity) and C(max) were 108.23% (101.90 a 114.95%), 108.11% (101.91 a 114.68%) and 99.71% (90.18 a 110.25%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products an the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that two medications of cetirizine are bioequivalent and, thus, may be prescribed interchangeably.     

Comparative bioavailability study with two gemfibrozil tablet formulations in healthy volunteers

OBJECTIVE: To assess the bioequivalence of gemfibrozil (CAS 25812-30-0) 900 mg tablet formulation from EMS Farmaceutica as test formulation versus a 900 mg tablet formulation as reference in 36 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval. Plasma samples were obtained over a 24-h period. Plasma gemfibrozil concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with negative ion electrospray ionization using multiple reaction monitoring (MRM). From the gemfibrozil plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: AUClast, AUC(0-inf) and Cmax. RESULTS: The limit of quantification was 0.05 microg/mL for plasma gemfibrozil analysis. The geometric mean and respective 90% confidence interval (CI) of Test/Reference percent ratios were 90.29 (81.39-100.17) for Cmax, 96.26 (90.33-102.59) for AUClast, 96.04 (90.21-102.23) for AUC(0-24 h) and 96.62 (90.82-102.78) for AUC(0-infinity). CONCLUSION: Since the 90% CI for AUClast, AUC(0-inf) and Cmax, ratios were within the 80-125% interval proposed by the U.S. FDA, it was concluded that gemfibrozil 900 mg tablet (test formulation) was bioequivalent to the 900 mg tablet reference formulation for both rate and extent of absorption.     

Comparative bioavailability study with two chlorpropamide tablet formulations in healthy volunteers

OBJECTIVE: The aim of this study was the assessment of the bioequivalence of two formulations (250 mg tablet) of chlorpropamide (CAS 94-20-2) in 36 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 3-week washout interval. Plasma samples were obtained over a 72-h period. Plasma chlorpropamide concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the chlorpropamide plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: AUC(0-72h), AUC(inf) and C(max). RESULTS: The limit of quantification was 0.1 microg/mL for plasma chlorpropamide analysis. The geometric mean and respective 90 % confidence interval (CI) of Test/ Reference percent ratios were 93.99% (87.11%-101.41%) for C(max), 92.45% (85.96%-99.44%) for AUC(0-72h) and 90.30% (83.35%-97.82%) for AUC(0-inf). CONCLUSION: Since the 90 % CI for AUC(0-72h), AUC(0-inf) and C(max) ratios were within the 80-125%interval proposed by the US FDA, it was concluded that chlorpropamide 250 mg tablet (test formulation) was bioequivalent to the reference 250 mg tablet for of both the rate and extent of absorption.     

Isosorbide dinitrate plasma concentrations and bioavailability in human subjects after administration of standard oral and sublingual formulations

The bioavailability of isosorbide dinitrate from formulations containing 5, 10, and 20 mg in tablets and 10 mg in solution for oral use and 5 mg in tablets for sublingual use, has been compared. When adjusted for dose, the peak mean plasma drug concentrations after oral administration were similar (e.g., 9.2 ng/mL after a 10-mg tablet) and about one-half that obtained after sublingual administration. Drug concentrations declined monoexponentially with mean half-lives ranging from 25-36 min. The relative bioavailability of isosorbide dinitrate from the oral formulations was not significantly different (p greater than 0.05) over the dose range studied, whereas the relative bioavailability after sublingual administration was about twice as great (p less than 0.01) as that after oral administration. The plasma drug concentration-time profile after administering the 5-mg sublingual tablet was similar to that obtained after administering orally a solution containing 10 mg, indicating that the latter should be as clinically effective as the former.     

Comparative bioavailability study of two phenoxymethylpenicillin potassium tablet formulations in healthy volunteers

OBJECTIVE: The aim of this study was to evaluate the performance of 2 phenoxymethylpenicillin 500,000 UI tablet formulations in healthy human volunteers. MATERIAL AND METHODS: The study was conducted using an open, randomized crossover design with a 7-day washout interval. A single dose of each formulation was administered to 26 healthy volunteers as assessed by clinical and laboratory test evaluations. The plasma samples were obtained over an 8-h interval and phenoxymethylpenicillin concentrations were quantified by a suitable and validated HPLC-UV method with detection at 220 nm. Systolic and diastolic blood pressure and pulse rate measurement were taken pre dose and at intervals up to 8 h. RESULTS: Tolerance of both products was adequate. The mean of Meracilina/Pen-Ve-Oral 500,000 UI% geometric mean was 99.89% for AUC0-t, 100.86% for AUC0-infinity and 101.11% for Cmax. The 90% confidence intervals were 94.62 - 105.46%, 95.22 - 106.83% and 98.61 - 103.87%, respectively. The mean recovery of phenoxymethylpenicillin was 94.8%, while the retention time observed for phenoxymethylpenicillin and phenytoin (internal standard) was 4 and 10 min, respectively. The limit of quantification was 0.10 mg/l. CONCLUSION: Since the 90% CI for AUC0-t, AUC0-infinity and Cmax ratios were all within the 80 - 125% interval proposed by the US FDA and accepted by ANVISA, it was concluded that the Meracilina formulation (manufactured by AchA(c) S.A.) is bioequivalent to Pen-Ve-Oral (manufactured by Eurofarma) for both the rate and the extent of bioavailability.     

Bronchodilator effect of sublingual isosorbide dinitrate in asthma

Summary The bronchodilating effect of 5 mg sublingual isosorbide dinitrate (ISDN) was studied in 10 patients with bronchial asthma, using the doubleblind randomised cross-over method with matched placebo. In a further 20 asthmatics the effect of sublingual ISDN was compared with that of metaproterenol given by a metered dose inhaler to a total dose of 2.25 mg, again using the cross-over method. The forced oscillation method was used to measure respiratory resistance (Rrs) and spirometry was used to measure vital capacity (VC) and forced expiratory volume in one second (FEV₁). 5 minutes after administration of ISDN Rrs had decreased (p<0.05) and VC (p<0.01) and FEV₁ (p<0.01) were significantly increased. The changes were still present after 15, 30 and 60 min. The placebo had no significant effect. ISDN increased FEV₁ less than metaproterenol, and the difference between them was statistically significant (p<0.05). However, there was no significant difference between ISDN and metaproterenol in the improvement in Rrs and VC. Of the total of 30 patients, 11 experienced headache and 4 had transient hypotension after ISDN administration. These side effects subsided spontaneously. It was concluded that sublingual ISDN had a bronchodilating effect in stable asthmatics.     

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.     

Comparative bioavailability of two sertraline tablet formulations after single-dose administration in healthy Thai volunteers

OBJECTIVE: To compare the bioavailability of two sertraline tablet (50 mg) formulations (Serlift from Ranbaxy Laboratories Ltd., Gurgaon Haryana, India, as a test formulation and Zoloft from Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia, as a reference formulation) in 24 healthy Thai male volunteers under fasting condition. MATERIALS AND METHODS: A randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover study with a washout period of 3 weeks, was conducted in 24 healthy Thai male volunteers. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours following drug administration. Plasma concentrations of sertraline were determined using validated LC-MS/MS method. Noncompartmental pharmacokinetics and statistical analyses were performed using SAS software for Windows, release 9.1 (SAS Institute Inc., Cary, NC, USA). RESULTS: The ratio of least square means and the 90% confidence intervals (CI) of the log-transformed data were 0.9950 (0.9111-1.0866) for Cmax, 1.0153 (0.9576-1.0764) for AUC(0-t) and 1.0110 (0.9510-1.0747) for AUC(0-infinity). In addition, the median tmax values for the test and reference formulations were similar (5.00 h). The 90% CI for Cmax, AUC(0-t) and AUC(0-infinity) were within the 0.8-1.25 interval of the US-FDA. CONCLUSIONS: The test formulation (Serlift, Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India) is bioequivalent to the reference formulation (Zoloft, Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia) both in terms of rate and extent of absorption after single-dose administration under fasting condition.     

甲磺酸倍他司汀片在健康人体的相对生物利用度

目的研究国产和进口甲磺酸倍他司汀片(抗眩晕药)的相对生物利用度。方法 20名健康志愿者随机、交叉单剂口服国产和进口甲磺酸倍他司汀片24 mg。用高效液相色谱-串联质谱法测定血浆中倍他司汀代谢产物 2-吡啶乙酸的浓度,计算2制剂的药代动力学参数及相对生物利用度,并进行生物等效性评价。结果 2-吡啶乙酸的实测tmax分别为(1．1±0．5),(1．0 ±0．4)h;Cmax分别为(358．88±93．44),(360．99±62．88)ng·mL-1;用梯形法计算所得的AUC0-t分别为(1687．01±400．51),(1591．43±352．05)ng·h ·mL-1。国产甲磺酸倍他司汀的相对生物利用度为(108．3±24．1)％。结论 2种制剂具有生物等效性。     

Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations.

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.     

奥沙普秦分散片的人体相对生物利用度

目的 :研究奥沙普秦分散片在健康人体的相对生物利用度 ,为临床更合理用药提供理论依据。方法 :采用 HPL C法测定了 18名健康志愿者口服奥沙普秦分散片和普通片各 40 0 m g后不同时间的血药浓度 ,并进行生物等效性评价。结果 :奥沙普秦分散片剂和普通片的 cmax分别为 ( 70 .5 8± 7.6 0 ) ︼g/ml和 ( 6 5 .89± 8.2 2 ) ︼g/ml;tmax分别为 ( 3.2 2± 0 .43) h和 ( 3.44± 0 .5 1)h;T1 / 2 分别为 33.18h和 2 9.41h;AUC(0 - 96h) 为 ( 2 741.6± 393.6 )︼g/ml· h和 ( 2 5 6 1.8± 375 .7)︼g/ml· h。奥沙普秦分散片剂的人体相对生物利用度为 ( 10 4.0 2± 4.0 5 ) %。结论 :奥沙普秦分散片剂与普通片具有生物等效性。