Bioequivalence of two oral formulations of nizatidine capsules in healthy male volunteers

PURPOSE: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and an innovator formulation of nizatidine 300 mg capsules under fasting conditions. METHODS: Twenty blood samples per period were collected from 20 healthy, Arab male volunteers over 16 h, plasma nizatidine concentrations were determined by HPLC assay, and pharmacokinetic parameters were determined by the non-compartmental method. RESULTS: Mean+/-SD C(max), T(max), AUC(0-->t), AUC(0-->infinity), and t1/2 were 2.96+/-0.54 and 3.28+/-0.68 microg/ml, 1.31+/-0.70 and 0.93+/-0.38 h, 9.04+/-1.66 and 9.03+/-1.94 microg x h/ml, 9.17+/-1.64 and 9.12+/-1.94 microg x h/ml, and 1.64+/-0.21 and 1.58+/-0.22 h for the generic and innovator formulation, respectively. The parametric 90% confidence intervals on the mean of the difference between log-transformed values were 98.06% to 103.21%, 98.74% to 103.71%, and 83.37% to 101.34%, for AUC(0-->t), AUC(0-->infinity), and C(max), respectively. CONCLUSION: The results indicate that these two formulations are equivalent in the rate and extent of absorption.     

Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

Bioequivalence study of two clopidogrel film-coated tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two clopidogrel 75 mg film-coated tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 24 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were assessed based on the concentrations of clopidogrel (CAS 120202-66-6) parent compound. In each of the two study periods (separated by a washout of one week) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 24 h (AUCt), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (t(max)), and the elimination half life (t1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for clopidogrel parent compound were 95.19% (81.63-110.90%) for AUCt, 95.55% (80.50-113.42%) for AUCinf, and 100.18% (80.87-124.09%) for Cmax. The 90% confidence intervals calculated for AUCt and Cmax of clopidogrel parent compound were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two clopidogrel film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

Bioequivalence of two recombinant granulocyte colony-stimulating factor formulations in healthy male volunteers

To evaluate the equivalence of the pharmacokinetic, pharmacodynamic and safety properties of two recombinant G-CSF formulations in healthy male volunteers, a standard 2-way randomized crossover double-blind study, with a 3 week washout period, was conducted. A single 300 microg G-CSF dose was administered subcutaneously. Hebervital (Heber Biotec, Havana, formulation A) and Neupogen (Hoffmann-La Roche S.A, formulation B) were compared. Twenty-four healthy male volunteers were included. The serum G-CSF level was measured by enzyme immunoassay (EIA) during the first 36 h after administration. Absolute neutrophils (ANC), white blood cells (WBC) and CD34+ cells counts were the pharmacodynamic variables measured up to 120 h. Other clinical and laboratory determinations were used as safety criteria. The pharmacokinetic parameters for formulation A and B were very close to each other (i.e. AUC, 235.9 vs 270.0 ng.h/ml; C(max), 29.2 vs 33.4 ng/ml; T(max), 4.2 vs 4.7 h; half-life, 3.2 vs 2.8 h; CL, 260.9 vs 277.2 ml/h; V(d), 1.2 vs 1.1 l; and MRT, 7.58 vs 7.38 h). The confidence intervals for the means ratio of all these parameters were within or very close to the 0.8-1.25 acceptance range. The pharmacodynamics showed high similarity since ANC and WBC had the same profiles for both products and no differences were detected for the estimated parameters. The CD34+ cells count increments were evident for both formulations in a similar way as well. The treatments were well tolerated. Registered adverse events were similar; back/spine pain was the most frequent. According to the overall results these formulations could be considered as clinically comparable.     

马来酸依那普利片的健康人体生物等效性

目的:研究马来酸依那普利片的人体相对生物利用度和生物等效性.方法:健康志愿者20名,随机双交叉单剂量口服马来酸依那普利片试验制剂和参比制剂,剂量分别为20 mg,用高效液相色谱(HPLC)法测定血浆中依那普利的浓度.用DAS药动学程序计算相对生物利用度并评价两种制剂生物等效性.结果:受试制剂与参比制剂的Cmax分别为(272.6±42.2)μg·L-1和(263.5±42.2)μg·L-1;tmax分别为(0.81±0.11)h和(0.80±0.10)h;AUC(0-∞)分别为(664.7±105.1)μg·h·L-1和(661.2±99.5)μg·h·L-1)AUC(0-inf)分别为(698.0±116.3)μg·h·L-1和(689.0±106.0)μg·h·L-1.试验制剂与参比制剂的人体相对生物利用度为(102.3±19.7)%,结论:试验制剂与参比制剂具有生物学等效性.     

Bioequivalence study of two different tablet formulations of carvedilol in healthy volunteers

OBJECTIVE: The aim of this study was to compare the extent and rate of absorption of two different carvedilol (CAS 72956-09-3) tablet formulations: 25 mg tablets, as the test formulation and the reference innovator product (25 mg tablets). METHODS: This study was designed as a single-dose, open-label, randomised, with a two-period and two-sequence crossover design, with blind determination of drug plasma concentration and a minimum 7-day washout period. Twenty-four healthy volunteers of both sexes were randomly assigned to treatment sequences. Carvedilol concentrations were determined in plasma samples obtained over a 24-h interval: baseline (pre-administration) and at 14 different times within the 24 h after administration. The analytical method, which used HPLC coupled with a MS/MS detector, was duly validated and the analytical assay was performed in compliance with Good Laboratory Practice (GLP). The limit of quantification (LOQ) was 0.50 ng/mL. Pharmacokinetic parameters representing the extent and/or rate of absorption (AUCinf, AUClast, and Cmax) were obtained. As secondary objective the tolerability of both formulations was also evaluated. RESULTS: The geometric mean of the test/reference formulations individual percent ratio was 98.14 % for AUCinf, 98.44 % for AUClast and 98.39 % for Cmax. The 90 % CI for the geometric mean of the individual ratio test/references formulations was 95.13 to 101.24 % for AUCinf, 95.23 to 101.76 % for AUClast, and 88.26 to 109.67 % for Cmax. CONCLUSIONS: The 90 % CI values obtained for AUCinf, AUClast, and Cmax are within the interval proposed by the EMEA/CPMP and the FDA as bioequivalence acceptance criteria, and consequently it can be conclude that the test formulation is bioequivalent with the reference formulation both in terms of rate and extent of absorption after single dose administration. The results from a previous pilot study allowed an optimal design for this trial.     

Bioequivalence of two rimantadine tablet formulations in healthy male volunteers after single dose administration

AIM: The bioequivalence of two rimantadine tablet formulations was determined. METHODS: The study was designed as a randomized, two-period, two-sequence, crossover study. Twenty-four healthy male volunteers received a single 100 mg dose of rimantadine hydrochloride as test (Rimantadin Lachema 100 tbl. obd., produced by Lachema, a.s., Brno, Czech Republic) and reference formulations (Elumadine 100 tbl. obd., produced by Forest Pharmaceuticals, St. Louis, USA). The two administrations were separated by 14 days and were performed in the fasting state. Blood samples were obtained at 15 time points during the interval 0-120 h after administration. Rimantadine plasma concentrations were determined by gas chromatography with electron-capture detection. RESULTS: The geometric mean concentration-time profiles of rimantadine after administration of the two formulations were superimposable. The following pharmacokinetic parameters refer to the geometric mean [exp(mean +/- SD)] values for the test and reference formulations, respectively: Cmax (ng/ml) 70.5 (60.0-82.7) vs. 70.0 (59.9 to 81.7), AUC(0-infinity) (ng x h/ml) 2872 (2224 to 3707) vs. 2849 (2195-3699), AUC(0-120 h) 2744 (2184-3448) vs. 2712 (2138-3441), t(1/2) (h) 25.8 (20.1-33.0) vs. 25.7 (20.6 to 32.1). Median (range) tmax (h) values were 4.5 (2.0-8.0) and 6.0 (2.0-8.0). Parametric 90% confidence intervals for the expected mean percentage ratios (test/reference) of the pharmacokinetic variables were within the range of 97% to 105%. The median (91.1% confidence interval) difference in tmax was -0.3 h (-2.0-0.5). The point and interval estimates were identical when truncated AUCs (0-96 h, 0-72 h, 0-48 h and 0-24 h) were used in calculations. CONCLUSION: The two rimantadine formulations were equivalent in both the rate and extent ofbioavailability and they were also well tolerated. This study confirms the findings of other studies showing that for immediate release formulations of drugs with long half-lives shortening the duration over which blood samples are collected improves the economics, is more ethical and does not impair the quality of data.     

萘哌地尔胶囊和片剂在中国健康男性志愿受试者的生物等效性比较

目的 :以萘哌地尔片剂为对照 ,研究萘哌地尔胶囊的人体药动学过程和生物等效性。方法 :1 8名健康成年男性志愿者采用随机分组自身交叉对照试验设计方法 ,采用HPLC 荧光检测 ,血样最低定量限为 1 μg·L- 1,平均绝对回收率 85 .2 %～ 89.9% ,日内、日间变异系数 (RSD)小于 8.0 5%。血浆标准曲线在 1 .56～ 40 0 μg·L- 1范围内相关性良好 ,r =1。结果 :萘哌地尔胶囊和片剂的主要药动学参数为 :Tmax:0 .63± 0 .2 4和 0 .57± 0 .2 1h;Cmax:1 2 9.1± 60 .7和 1 38.3± 72 .5μg·L- 1;T1 2 :5 .9± 1 .7和 6.4±2 .1h;AUC0 - 2 4 :2 95.6± 90 .9和 2 91 .6±89 .3μg·L- 1·h- 1;AUC0 -∞ :32 0± 97.2和 31 8.0±98.3μg·L- 1·h- 1。萘哌地尔胶囊的相对生物利用度F0 - 2 4 、F0 -∞ 分别为 1 0 1 .9%± 1 2 .9%和 1 0 1 .2 %±1 2 .3%。结论 :两种制剂生物等效     

Bioequivalence study of two different film-coated tablet formulations of losartan-hydrochlorothiazide in healthy volunteers

The study was conducted in order to assess the bioequivalence of two film-coated formulations containing 100 mg of losartan (CAS 124750-99-8) and 12.5 mg of hydrochlorothiazide (CAS 58-93-5). Seventy-three healthy subjects were enrolled in a randomised, single-dose, open-label, two-way crossover study, with a minimum washout period of 7 days. A total of 21 blood samples were collected up to 36 h post-dosing. Losartan, losartan carboxy acid and hydrochlorothiazide levels were determined by liquid chromatography with tandem mass detection (lower limit of quantification: 1.01 ng/mL for hydrochlorothiazide, 2.02 ng/mL for losartan and 2.51 ng/mL for losartan carboxy acid). Pharmacokinetic parameters used for bioequivalence assessment (AUC(0-t) and Cmax as primary and AUC(0-inf) as secondary pharmacokinetic parameters) were determined from the losartan and hydrochlorothiazide concentration data using non-compartmental analysis. Data from losartan carboxy acid was reported and presented as supportive data. The 90% confidence intervals (obtained by ANOVA) for losartan were 97.05-118.48% for Cmax 100.76-106.10% for AUC(0-t) and 100.80-106.10% for AUC(0-inf) whereas for hydrochlorothiazide the 90% confidence intervals obtained were 103.94-115.33% for Cmax, 101.97-109.61% for AUC(0-t) and 101.77-109.02% for AUC(0-inf), and for losartan carboxy acid the intervals obtained were 98.31-107.82% for Cmax, 97.89-104.30% for AUC(0-t) and 98.06-104.30% for AUC(0-inf). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined ranges (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.     

Bioequivalence study of two different coated tablet formulations of finasteride in healthy volunteers

This study was conducted in order to assess the bioequivalence of two different coated tablet formulations containing 5 mg finasteride (CAS 98319-26-7). Twenty-six healthy volunteers were enrolled in an open, randomised, crossover single dose study with 2 periods x 2 sequences and a minimum washout period of 7 days. Plasma samples were obtained over 24 h (at baseline, +0.5 h, +1 h, +1.5 h, +2 h, +2.5 h, +3 h, 3.5 h, +4 h, +4.5 h, +5 h, +6 h, +8 h, +10 h, +12 h, +16 h and +24 h after administration). Finasteride levels were determined by high-pressure liquid chromatography with tandem mass detection, HPLC-MS/ MS, (LOQ 0.50 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUClast and Cmax were main evaluation criteria, however, AUCinf was also analysed) were determined from the finasteride concentration data using non-compartmental analysis. The 90 % confidence intervals (obtained by ANOVA) were 86.31-98.69 for Cmax, 95.40-104.88 for AUClast and 96.20-105.81 for AUCinf that is, they were all within the predefined ranges. It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.     

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.     

马来酸依那普利口腔崩解片健康人体生物等效性研究

目的研究马来酸依那普利口腔崩解片与普通片在健康人体的生物等效性.方法20例健康志愿者采用双周期交叉实验,分别给予马来酸依那普利口腔崩解片(受试制剂)和片剂(参比制剂)各20mg, LC-MS/MS法测定健康受试者血清中依那普利及其代谢产物依那普利拉浓度,DAS2.0统计软件计算主要药动学参数.结果受试制剂和参比制剂中依那普利的主要药动学参数分别为t1/2(0.731±0.124)和(0.706±0.159)h,Cmax(170.3±44.7)和(180.0±37.2)μg·L-1,Tmax(0.863±0.309)和(0.850±0.297)h,AUC0～48h(269.5±67.2)和(268.7±67.6)μg·h·L-1.受试制剂和参比制剂中依那普利拉的主要药动学参数为t1/2(8.247±2.349)和(8.225±3.377)h,Cmax(73.8±20.8)和(79.1±21.5)μg·L-1,Tmax(3.450±0.686)和(3.400±0.754)h,AUC0～48h(605.6±124.7)和(640.6±146.0)μg·h·L-1.以依那普利和依那普利拉计算的人体相对生物利用度分别为(103.8±32.0)%和(96.5±17.9)%.结论2种制剂具有生物等效性.     

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.     

Bioequivalence evaluation of two sertraline tablet formulations in healthy male volunteers after a single dose administration

SUBJECTS, MATERIAL AND METHODS: According to a randomized two-period crossover design, 12 Chinese male volunteers were treated with 2 sertraline tablet formulations, one was made in China as test tablet, the other was made in England as reference tablet. Each volunteer received each sertraline in a single dose of 150 mg. The 2 medications were carried out by a wash-out phase of 23 days. Blood samples were obtained just before dosing and at 10 time points until 96 hours after administration, and plasma sertraline concentrations were determined by a sensitive gas-chromagraphy electron-capture method with a lower limit of quantification of 0.625 ng/ml. The bioequivalence of 2 formulations was evaluated by the shortest 90% confidence interval method which corresponds to the two one-sided test method. RESULTS: The point estimate (90% confidence interval) of the mean ratio (test/reference) for AUC(0-96) was 97.19% (82.66% to 122.33%), for Cmax 96.27% (83.64% to 121.36%), and for t(l/2) 96.31% (85.43% to 119.57%). Regarding Tmax (test-reference), the 90% confidence interval ranged from -4 to +4 hours, but the difference between the Tmax values of 2 products is clinically of minor importance. CONCLUSION: Therefore, it can be concluded that 2 sertraline tablet formulations are bioequivalent. administration, sertraline is slowly absorbed with peak plasma concentrations at 6 - 8 h, and has a terminal elimination half-life of approximately 26 h, indicating once-daily dosing is available. Clinically, it can be taken either in the morning or in the evening, with or without food [Ronfeld et al. 1997b]. In addition, it also exhibits higher plasma protein binding up to 97% and extensive first-pass metabolism. By demethylation, sertraline is metabolized primarily to N-demethylsertraline, and then eliminated by hydroxylation arid conjugation [Tremaine et al. 1989]. This study aimed at assessing of bioequivalence of two sertraline formulations (produced in China and England, respectively) in healthy male volunteers after a single dose administration.     

Psychotropic effects of enalapril maleate in normal volunteers

In order to establish any psychotropic effects of the angiotensin-converting enzyme inhibitor enalapril, the drug was administered in doses of 20 mg every morning for 14 days to 12 normal subjects, and compared with placebo on a battery of physiological, psychological and subjective tests, before and after the dose on the 1st and 14th days.Diastolic blood pressure was significantly reduced and heart-rate increased by enalapril as compared with placebo; one component (P ₁-N ₁) of the auditory evoked EEG response was increased and tapping rate quickened. The commonest side effect was tiredness.It was concluded that enalapril (unlike most other antihypertensive agents) did not lower mood but could enhance attention and alertness.     

伏立康唑片在中国健康男性体内的生物等效性研究

目的：研究伏立康唑在中国健康男性体内的药代动力学,并评价其相同剂量制剂的生物等效性。方法：19名健康男性志愿者分别单剂量交叉口服伏立康唑片受试制剂或参比制剂200mg,于服药前0h和服药后0．25、0．5、0．75、1、1．5、2、3、4、6、8、12、24、36h抽取4．0mL静脉血,采用高效液相色谱法测定血浆中伏立康唑的浓度。通过DASVer3．0软件计算主要的药动学参数,评价两种制剂的生物等效性。结果：伏立康唑片受试制剂与参比制剂的药动学参数分别为：AUC。（5304．967±3072．252）、（5130．968±2985．462）ng·mL^-1·h;AUC0-∞（5683．143±3438．261）、（5445．115±3181．161）ng·mL^-1·h;Cmax（925．728±356．11）、（1040．251±448：929）ng·mL^-1;tmax（1．566±0．975）、（1．382±0．959）h;t1/2（6.316±2．938）、（5．966±2．276）h。以AUC0-36计算,受试制剂对参比制剂的相对生物利用度为（100．5±3．4）％。结论：两种伏立康唑片在中国健康男性志愿者体内具有生物等效性。     

Pharmacokinetic and pharmacodynamic comparative study of zofenopril and enalapril in healthy volunteers

Zofenopril calcium (CAS 81938-43-4) is a new angiotensin converting enzyme (ACE) inhibitor, which in addition to the typical activity of the class, proved to possess a specific cardioprotective effect due also to the presence of the sulfhydryl group. In this trial zofenopril calcium and enalapril maleate (CAS 76095-16-4) were given to 20 healthy volunteers of both sexes in repeated dose regiment at two dose levels: 30 mg and 60 mg zofenopril calcium and 10 mg and 20 mg enalapril maleate. The study was conducted according to a two-period, two-sequence, crossover design, with washout. ACE activity in serum and zofenopril, zofenoprilat, enalapril and enalaprilat plasma concentrations were determined during and on the last day of the two study periods. Both zofenopril and enalapril were extensively converted through hydrolysis to their active metabolites zofenoprilat and enalaprilat, respectively. Zofenopril exhibited a complete and a more rapid hydrolysis rate compared to enalapril, which is reflected by the higher metabolite to parent drug ratio of Cmax and AUCss, tau showed by this compound. Even though only two dose levels were investigated in this trial, the pharmacokinetics of both drugs seem to be linear. In line with previous trials, both compounds at both dose levels investigated produced complete or almost complete inhibition of ACE activity in serum, for a period lasting 6-8 h after administration, the inhibition being still relevant 24 h thereafter. The tolerability of the two drugs at both dose levels proved to be very good as demonstrated by subjective and objective symptoms, by the absence of relevant adverse events, and by laboratory biochemical parameters and vital signs evaluated before and after the trial. Blood pressure showed a fairly decreasing trend with both the drugs, systolic and diastolic blood pressure values being however within normal range in all the subjects. In no case symptoms of hypotension were experienced. In conclusion, zofenopril calcium and enalapril maleate show very good tolerability and appear to exert similar activity on serum ACE. The main difference in the pharmacokinetics of the two compounds is the conversion from pro-drug to the active metabolite which is faster with zofenopril.