Bioavailability of two single-dose oral formulations of omeprazole 20 mg: an open-label, randomized sequence, two-period crossover comparison in healthy Mexican adult volunteers

BACKGROUND: Omeprazole is a proton-pump inhibitor that acts to reduce acid secretion in the stomach and is used for treating various acid-related gastrointestinal disorders. There are several generic formulations of omeprazole available in Mexico; however, a literature search failed to identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of this study was to compare the bioavailability of 2 oral formulations of omeprazole 20-mg capsules, marketed for use in Mexico, in healthy volunteers: Inhibitron (test formulation) and LosecA 20 mg (reference formulation). METHODS: This study used a single-dose, open-label, randomized sequence, 2 x 2 crossover (2 administration periods x 2 treatments) design to compare the 2 formulations. Eligible subjects were healthy adult Mexican volunteers of both sexes. Subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test formulation followed by the reference formulation, or vice versa, with a 7-day washout period between administration periods. After a 12-hour (overnight) fast, subjects received a single, 20-mg dose of the corresponding formulation. Plasma samples were obtained over a 12-hour period after administration. Plasma omeprazole concentrations were analyzed by a nonstereospecific high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to time t (AUC(0-t)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and 0.17, 0.33, 0.50, 0.75, 1, 1.25, 1.50, 1.75, 2, 2.50, 3, 4, 6, 8, and 12 hours after administration. The formulations were considered bioequivalent if the natural log (ln)-transformed ratios of C(max) and AUC were within the predetermined equivalence range of 80% to 125%, and if P 相似文献   

Bioavailability of two oral suspension and two oral tablet formulations of acyclovir 400 mg: two single-dose, open-label, randomized, two-period crossover comparisons in healthy Mexican adult subjects

BACKGROUND: Acyclovir is an important antiviral drug, used extensively for treatment of herpes simplex and varicella zoster. Six oral generic formulations of acyclovir are available in Mexico; however, a literature search failed to identify data information concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability of 4 oral formulations of acyclovir 400 mg--2 tablet formulations and 2 suspension formulations--with their corresponding listed drug references in Mexico (a list issued by Mexican Health Authorities). METHODS: Two separate, single-dose, open-label, randomized, 2-period crossover studies were conducted at the Centro de Estudios Científicos y Clínicos Pharma, S.A. de C.V. (clinical unit), Mexico City, Mexico. For each study, a different set of eligible subjects were selected. They included healthy Mexican volunteers of either sex. For each study, subjects were randomly assigned to receive 1 test formulation of acyclovir 400 mg followed by the reference formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour (overnight) fast, subjects received a single 400-mg dose (tablet or 10-mL suspension) of the corresponding formulation. For the analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to time t (AUC(0-t)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the natural logarithm (ln)-transformed ratios of Cmax and AUC were within the predetermined equivalence range of 80% to 125% and if P 相似文献   

Bioavailability of two oral formulations of loratadine 20 mg with concomitant ketoconazole: an open-label, randomized, two-period crossover comparison in healthy Mexican adult volunteers

BACKGROUND: Loratadine is a long-acting antihistamine with selective peripheral histamine H(1)-receptor antagonistic activity and fewer sedative effects compared with conventional antihistamines, and is widely used in Mexico. Although several generic formulations of loratadine are available in Mexico, based on a literature search, information concerning the bioavailability of each formulation in the Mexican population is not available. OBJECTIVE: The aim of this study was to compare the bioavailability and tolerability of 2 oral formulations of loratadine 20 mg (two 10-mg tablets) used in Mexico: Sensibit (test formulation; Laboratorios Liomont S.A. de C.V., Mexico City, Mexico) and Clarityne (reference formulation; Schering-Plough S.A. de C.V., Mexico City, Mexico) in healthy volunteers. METHODS: This open-label, randomized, 2-period crossover study was conducted at Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico. Eligible subjects were healthy male Mexican volunteers aged > or=18 years. Subjects were randomly assigned to receive a single 20-mg dose (two 10-mg tablets) of the test or reference formulation, followed by a 2-week washout period, followed by the same dose of the alternate formulation. A 400-mg dose of ketoconazole (2 doses in 24 hours) was administered to each subject before the administration of each formulation, and a 200-mg dose of ketoconazole was given together with each formulation (ie, a total of 600 mg of ketoconazole was administered). Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C(maX), AUC(0-t), and AUC(0-infinity), blood samples were drawn at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 5, 8, 12, 16, and 22 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of C(maX) and AUC were within the predetermined equivalence range of 80% to 125%. Tolerability was assessed by monitoring vital signs and subject interview regarding the potential presence of adverse events (AEs). RESULTS: Thirty-two subjects were enrolled in the study (mean age, 22 years [range, 18-28 years]; mean weight, 68.9 kg [range, 58-79 kg]; mean height, 170.8 cm [range, 158-183 cm]). Sixteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding ratios of CmaX, AUC(0-t), and AUC(0-infinity) were 81.43% to 106.01%, 83.12% to 100.23%, and 84.06% to 101.10% (all, P < 0.05), meeting the predetermined criteria for bioequivalence. Similar results were found for data without a logarithmic transformation. No AEs were reported throughout the study. CONCLUSIONS: In this small study in healthy Mexican volunteers, a single, 20-mg dose of the test formulation of loratadine was found to be bioequivalent to that of the reference formulation based on the rate and extent of absorption when concomitantly administered with ketoconazole. Both formulations were well tolerated.     

Bioavailability of two sublingual formulations of ketorolac tromethamine 30 mg: a randomized, open-label, single-dose, two-period crossover comparison in healthy Mexican adult volunteers

BACKGROUND: Ketorolac tromethamine (ie, ketorolac) is an NSAID that appears to have several mechanisms of action, including inhibition of prostaglandin synthesis, modulatory effect on opioid receptors, and nitric oxide synthesis. Ketorolac is used in the treatment of pain. There are various generic formulations of sublingual ketorolac available in Mexico. However, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of this study was to compare the bioavailability of 2 sublingual formulations of ketorolac 30-mg tablets in healthy Mexican adult volunteers. METHODS: This was a randomized-sequence, open-label, single-dose, 2-period crossover (2 dosing periods x 2 treatments) study comparing the bioavailability of two 30-mg sublingual tablet formulations of ketorolac. Healthy Mexican adult (aged, 18-55 years) men and women were eligible for inclusion. Subjects were randomly assigned in a 1:1 ratio to receive a single dose of the test formulation or the reference formulation. After a 12-hour overnight fast, subjects received a single dose of the corresponding formulation. There was a 7-day washout period between administration periods. Plasma samples were obtained over a 24-hour period after administration. Plasma ketorolac concentrations were analyzed by high-performance liquid chromatography for analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity. Blood samples were drawn immediately after sublingual placement of the drug and at 10, 20, 30, 40, 50, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of Cmax and AUC were within the predetermined range of 80% to 125% and if P for the 90% CIs was <0.05. Tolerability was assessed by vital sign monitoring, laboratory analysis results, and subject interviews. RESULTS: A total of 27 subjects (18 women, 9 men; mean [SD] age, 27 [9] years [range, 18-47 years]; weight, 61 [8] kg [48-79 kg]; height, 163 [8] cm [150-180 cm]) were enrolled and completed the study. Fourteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding differences in natural log Cmax, AUC0-24, and AUC0-infinity were 95.94% to 114.66%, 98.34% to 105.90%, and 99.25% to 108.36%, respectively (all, (P) < 0.05), meeting the predetermined criteria for bioequivalence. Sixteen subjects experienced a total of 20 adverse events (AEs) during the study. None of the AEs were considered serious. One AE (nausea) appeared to be related to use of the reference formulation. Conclusions: In this small study in 27 healthy Mexican adult volunteers, the test formulation of a single, 30-mg sublingual tablet of ketorolac appeared to be bioequivalent to the reference formulation based on the rate and extent of absorption. Both formulations were well tolerated.     

Bioavailability of two oral formulations of a single dose of levofloxacin 500 mg: An open-label,randomized, two-period crossover comparison in healthy mexican volunteers

Background: Levofloxacin is a synthetic fluoroquinolone with a broad spectrum of antibacterial activity. It is indicated for the treatment of respiratory, sinus, skin, and urinary tract infections. Although generic formulations of oral levofloxacin are marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations; these data would be relevant to secure marketing of a test formulation in Mexico.Objective: The aim of this study was to compare the bioavailability and determine the bioequivalence of a test formulation (an oral tablet containing levofloxa-cin 500 mg) with its corresponding listed reference-drug formulation in Mexico (a list issued by Mexican Health Authorities).Methods: A single-dose, open-label, randomized-sequence, 2-period crossover design was used in this study. Eligible participants were healthy Mexican adults of either sex, randomly assigned to receive the test formulation followed by the corresponding reference formulation, or vice versa, with a 1-week washout period between doses. After a 10-hour overnight fast, the participants received the assigned formulation. Plasma concentrations of levofloxacin were determined using high-performance thin-layer chromatog-raphy, and densitometric analysis was performed at 300 nm. For the analysis of pharmacokinetic parameters, including C_max, AUC0_–24, and AUC_0?∞), blood samples were drawn at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. The test formulation was considered to meet the criteria for bioequivalence if the geometric mean ratios (test/reference) were with- in the predetermined range of 80% to 125%. Tolera-bility was determined by clinical assessment, vital signs, laboratory analysis, and interviews with participants about adverse events.Results: A total of 26 participants were enrolled, including 14 men and 12 women with a mean (SD) age of 24 (4) years (range, 18–34 years), weight of 62.2 (10.0) kg (range, 45.5–80.0 kg), height of 163 (9) cm (range, 148–176 cm), and body mass index of 23.3 (2.4) kg/m² (range, 19.2–27.1 kg/m²). The 90% CIs for log-transformed C_max, AUC_0–24, and AUC_0?∞ were 94.48% to 106.22%, 90.01% to 116.44%, and 85.11% to 114.00%, respectively. Eleven participants reported a total of 20 adverse events during the study. None of the adverse events were considered serious.Conclusions: In this small study in healthy, fasting Mexican adults, a single 500-mg dose of the test formulation of orally administered levofloxacin met the regulatory requirements to assume bioequivalence based on the rate and extent of absorption. Both formulations were well tolerated.     

Bioavailability and bioequivalence of two oral formulations of alendronate sodium 70 mg: An open-label,randomized, two-period crossover comparison in healthy Korean adult male volunteers

Background: Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence.Objectives: The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population.Methods: This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC_0?t, AUC_0?∞, C_max, T_max, t_1/2, and the elimination constant (k_e), were determined using noncompart-mental analysis. The formulations were considered bioequivalent if the 90% CI ratios for C_max and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA).Results: Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19–28 years]; height, 175.9 [5.4] cm [range, 162.0–185.0 cm]; and weight, 71.2 [9.5] kg [range, 61–96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC_0?t, AUC_0?∞ and C_max were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T_max was 1.09 hours (0.5–2.0 hours), and the mean (SD) of t_1/2 and k_e were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study.Conclusions: Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC_0?t, AUC_0?∞, and C_max were found in this healthy Korean adult male population.     

Bioequivalence and pharmacokinetic evaluation of two branded formulations of aceclofenac 100 mg: a single-dose, randomized, open-label, two-period crossover comparison in healthy Korean adult volunteers

BACKGROUND: Aceclofenac is a phenylacetic acid derivative with analgesic and anti-inflammatory properties and an improved gastrointestinal tolerance compared with other NSAIDs, such as diclofenac. OBJECTIVE: This study was conducted to compare the bioavailability of 2 branded formulations of aceclofenac 100 mg (test and reference) marketed in Korea. Methods: This single-dose, randomized, open-label, 2-period crossover study in healthy Korean adult volunteers was conducted at Hanyang University Medical Center (Seoul, Republic of Korea). Subjects received 1 tablet of each aceclofenac 100-mg formulation. Study drugs were administered with 240 mL of water after a 10-hour overnight fast on each of 2 treatment days separated by a 1-week washout period. After study drug administration, serial blood samples were collected over a period of 12 hours. Plasma was analyzed for aceclofenac concentration using a validated high-performance liquid chromatography method with visible detection in the range of 0.1 to 20 microg/mL, with a lower limit of quantitation of 0.1 microg/mL. Several pharmacokinetic (PK) parameters, including C(max), T(max), t(1/2), AUC(0-t), AUC(0-infinity), and k(e), were determined from the plasma concentrations of the 2 aceclofenac formulations. C(max), AUC(0-t), and AUC(0-infinity) were used to test for bioequivalence after log-transformation of plasma data. The predetermined, regulatory range of 90% CI for bioequivalence was 0.80 to 1.25. RESULTS: A total of 24 subjects were enrolled (20 men, 4 women; mean [SD] age, 23.5 [1.4] years; mean [SD] weight, 68.1 [11.5] kg). No significant differences were found based on analysis of variance, with mean values and 90% CIs of test/reference ratios for these parameters as follows: C(max), 10.57 versus 9.79 microg/mL (0.961-1.225); AUC(0-t), 19.95 versus 19.93 microg x h/mL (0.937-1.037); and AUC(0-infinity), 20.75 versus 20.48 microg x h/mL (0.949-1.049). CONCLUSION: In these healthy Korean volunteers, results from the PK analysis suggested that the test and reference formulations of aceclofenac 100-mg tablets were bioequivalent, based on the regulatory definition.     

A randomized, open-label pharmacokinetic comparison of two oral formulations of fluconazole 150 mg in healthy adult volunteers

BACKGROUND: Because of its systemic action, fluconazole is prescribed for a variety of fungal infections. However, therapeutic failure might result when a patient is switched between an innovator drug and a nonbioequivalent generic formulation. Pharmacokinetic (PK) studies investigating the bioequivalence of generic and innovator drugs can minimize such risks. OBJECTIVE: The aim of this study was to compare the PK profiles and relative bioavailabilities of 2 oral formulations of fluconazole: Diflucan (reference; Pfizer Corporation Austria GmbH, Wien, Austria) and Funzol (test; Bosnalijek d.d., Pharmaceutical and Chemical Industry, Sarajevo, Bosnia and Herzegovina), both prepared as capsules containing 150 mg of active drug. METHODS: A single oral dose of fluconazole was given under fasting conditions to healthy, white volunteers aged 18 to 55 years in this open-label, randomized, crossover study. A 3-week washout period was applied between each of the 2 doses. Serum samples were obtained before dosing and at various time points after dosing up to 144 hours and were analyzed for fluconazole concentration using a high-performance liquid chromatography-UV method. PK parameters representing the extent (AUC(0-infinity)) and rate (CmaX and T(max)) of absorption of fluconazole were obtained. An analysis of variance, a power analysis, 90% CI, and two 1-sided tests were used for statistical analysis of relative differences between the 2 drugs. Bioequivalence was concluded if the 90% CIs for the geometric mean ratios of AUC(0-infinity) and C(max) were between 0.80 and 1.25. A study investigator monitored the volunteers for adverse effects at 5 defined time points during the clinical part of the investigation. RESULTS: Thirteen men and 11 women (mean age, 33.3 years; mean weight, 73.6 kg) completed the study. The respective point estimates of the ratios of geometric means of log-transformed C(max) and AUC0(0-infinity) of fluconazole (test vs reference) were 0.985 and 1.047, with 90% CIs of 0.894 to 1.085 and 0.927 to 1.182, respectively. Differences in T(max) also did not reach statistical significance. No adverse effects were reported by the subjects or revealed by clinical or laboratory tests. CONCLUSIONS: The study failed to demonstrate any statistically significant differences in C(max) and AUCO(0-infinity) values between the test and reference formulations of oral fluconazole 150 mg in this small, select population of healthy volunteers. On that basis, and according to both the rate and extent of absorption, the test and reference formulations were considered bioequivalent.     

A randomized, open-label, two-period, crossover bioavailability study of two oral formulations of tacrolimus in healthy Korean adults

BACKGROUND: Tacrolimus is a macrolide immunosuppressant used in transplantation. It has been shown to have a comparable therapeutic effect and a low adverse drug reaction profile relative to cyclosporme. OBJECTIVE: The present study compared the pharmacokinetics of twice-daily doses of 2 tacrolimus formulations used in clinical practice in Korea: a conventional (reference) formulation and a more recently developed (test) formulation. The bioavailability of the 2 formulations was evaluated based on the requirement of 20% deviation at a power of 80%. METHODS: This study had a randomized, open-label, 2-period, crossover, non-inferiority design. There was a 96-hour treatment period for each formulation, with a 3-week washout period between formulations. Each healthy adult subject received two 1-mg capsules of the reference or test formulation of tacrolimus twice daily (morning and evening), for a total daily dose of 4 mg. Blood samples were obtained during the 96-hour period after the first dose in each treatment period, with tolerability assessments performed up to 2 weeks after the first dose in each period. The primary pharmacokinetic parameters were C(max) and AUC from time 0 to the last measured concentration and extrapolated to infinity. Secondary pharmacokinetic parameters were T(max), t(1/2), C(min0-24), AUC(0-24), and C(96). RESULTS: The study enrolled 29 healthy Korean volunteers (22 men, 7 women; mean [SD] age, 29 [7] years; age range, 20-51 years; mean weight, 66 [10] kg; mean height, [171 17] cm). All volunteers completed both treatment periods. The 90% Cls for the ratios of the pharmacokinetic parameters (test:reference drug) were 119.25-161.29 for C(max), 95.29-129.04 for AUC(0-t), and 95.63-131.42 for AUC(0-infinity). Based on the 80% to 125% bioequivalence criterion, these results indicated that pharmacokinetic exposure to the test drug was not inferior to that of the reference drug. Both formulations were well tolerated, with no serious adverse events reported. CONCLUSION: In these healthy Korean adults, there were no statistically significant differences between the pharmacokinetic parameters of the more recently developed oral formulation of tacrolimus and the conventional formulation.     

Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects

BACKGROUND: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility-and improved stability against long-term stability test and accelerated temperature test-compared with the conventional formulation (amlodipine besylate). OBJECTIVE: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects. METHODS: This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed. RESULTS: All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20-25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57-77 kg). The plasma concentration-time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration-time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study. CONCLUSIONS: The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects.     

Bioequivalence of single 100-mg doses of two oral formulations of topiramate: An open-label,randomized-sequence,two-period crossover study in healthy adult male Mexican volunteers

Background: The proprietary form of topiramate is indicated in Mexico as an antiepileptic agent and in the prophylaxis of migraine headaches. However, before generic topiramate is placed on the market, pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed.Objective: The aim of this study was to compare the bioequivalence and tolerability of a generic (test) and a branded (reference) formulation of topiramate 100 mg in healthy Mexican volunteers.Methods: This open-label, randomized-sequence, 2-period crossover study was conducted at Ipharma SA de CV, Monterrey, Mexico. Eligible subjects were healthy male Mexican volunteers aged 18 to 45 years. Participants were randomly assigned to receive 100 mg of the test or reference formulation, followed by a 3-week washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C_max, AUC_0-t, and AUC_0-∞, blood samples were obtained over a 144-hour period after dosing. The formulations were to be considered bioequivalent if calculations of a 90% CI for the ratio of the means of the measures for the test and reference formulations fell within bioequivalence limits, 80% to 125%, for logarithmic (log) transformation of C_max and AUC, and if two 1-sided t tests showed P < 0.05. Tolerability was assessed using vital sign measurement (blood pressure, body temperature, heart rate, and respiratory rate), laboratory analysis (hematology, blood biochemistry, hepatic function, and urinalysis), and subject interview.Results: Twenty-eight men (mean age, 22.21 years [range, 18–28 years]; mean weight, 75.04 kg [range, 62–96 kg]; mean height, 177 cm [range, 163–192 cm]) were enrolled in this study, and 28 (14 each randomized to receive the test or reference formulation first) completed it. No period or sequence effects were observed. The 90% CIs for the log-transformed C_max, AUC_0-t and AUC_0-∞ were 94.70 to 112.05, 98.88 to 105.16, and 98.80 to 105.28, respectively (all, P < 0.05). No adverse events were reported by the volunteers or found on clinical laboratory testing during the study.Conclusions: This study did not find any statistically significant differences in C_max or AUC values between the test and reference formulations of oral topiramate 100 mg in this population of healthy adult male Mexican volunteers. On that basis, and according to both the rate and extent of absorption, the test and reference formulations met the regulatory criteria for bioequivalence. Both formulations were well tolerated.     

Bioequivalence evaluation of two capsule formulations of amoxicillin in healthy adult male bangladeshi volunteers: A single-dose, randomized, open-label, two-period crossover study

Background: Amoxicillin, a semisynthetic penicillin antibiotic, is widely prescribed in Bangladesh due to its extended spectrum and its rapid and extensive oral absorption with good tolerability. Although a number of generic oral formulations of amoxicillin are available in Bangladesh, a study of the bioequivalence and pharmacokinetic properties of these formulations has not yet been conducted in a Bangladeshi population.Objective: The aim of this study was to assess the pharmacokinetic properties and bioequivalence of 2 formulations of amoxicillin 500-mg capsules (test, SK-mox^®; reference, Amoxil-Bencard^®) using serum data.Methods: This single-dose, randomized, open-label, 2-period crossover study was conducted in healthy male subjects in compliance with the Declaration of Helsinki and International Conference on Harmonisation guidelines. Subjects were assigned to receive the test or the reference drug as a single-dose, 500-mg capsule under fasting conditions after a 1-week washout period. After oral administration, blood samples were collected and analyzed for amoxicillin concentration using a validated high-performance liquid chromatography method. The pharmacokinetic parameters were determined using a noncompartmental method. The formulations were considered bioequivalent if the natural log-transformed ratios of pharmacokinetic parameters were within the predetermined equivalence range of 80% to 125%, according to the US Food and Drug Administration (FDA) requirement.Results: Twenty-four healthy adult male Bangladeshi volunteers (mean [SD] age, 26.92 [3.37] years; age range, 23–34 years; mean [SD] body mass index, 23.O9 [1.58] kg/m²) participated in the study. Using serum data, the values obtained for the test and reference formulations, respectively, were as follows: C_max, 9.85 (2.73) and 10.63 (2.12) μg/mL; T_max, 1.29 (0.58) and 1.33 (0.49) hours; and AUC_0–12, 27.09 (7.62) and 28.56 (6.30) μg/mL · h⁻¹. No period, sequence, or formulation effects were observed; however, significant variation was found among subjects with regard to AUC_0–12 (P < 0.001), AUC_0−∞ (P = 0.002), area under the moment curve (AUMC) from 0 to 12 hours (P < 0.001), and AUMC_0−∞ (P = 0.017). All CIs for the parameters measured were within the FDA-accepted limits of 80% to 125%.Conclusion: The present study suggests that the test 500-mg amoxicillin capsule was bioequivalent to the reference 500-mg capsule according to the FDA regulatory definition, in this population of healthy adult male Bangladeshi volunteers.     

Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A randomized,open-label,single-dose,fasting, two-period,two-sequence crossover comparison in healthy male South American volunteers

Background: Imatinib is a tyrosine kinase inhibitor that has been established as a highly effective therapy for chronic myelogenous leukemia and gastrointestinal stromal tumors. A new generic, once-daily 400-mg tablet of imatinib has been developed by a pharmaceutical company in Argentina, where the regulatory standard for marketing authorization of an imatinib generic is in vitro dissolution testing.Objective: The aim of this study was to assess the bioequivalence of a new generic film-coated test tablet formulation versus a film-coated reference tablet formulation of imatinib 400 mg. The local manufacturer seeks to validate the in vitro performance of this new formulation with a bioequivalence study.Methods: A randomized, open-label, single-dose, fasting, 2-period, 2-sequence crossover design with a 2-week washout period was used in this study. The study population consisted of healthy male South American (Uruguayan) volunteers, who were assigned in a 1:1 ratio to a randomized sequence (test-reference or reference-test). In each period, the test or reference formulation was administered after an overnight fast. During the 72-hour follow-up period, participants were monitored for vital signs and symptoms. Blood samples were collected at 15 time points, including baseline, until 72 hours. Physical examination and laboratory tests (blood, urine) were repeated 1 week after study completion. A noncompartmental model was used to determine the pharmacokinetic parameters of imatinib. The 90% CIs of the test/reference ratios for AUC_0-∞ and C_max were determined; the test and reference formulations were considered bioequivalent if the 90% CIs were between 0.80 and 1.25. Adverse events were assessed by a nurse who administered a questionnaire while the healthy volunteers were admitted in the unit.Results: The bioequivalence study was conducted in 30 Uruguayan male volunteers. Demographic characteristics (mean [SD]) included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71 (0.09) m; and body mass index, 24.3 (3.0) kg/m2. The mean (SD) of AUC_0-∞ was 38,179 (15,504) ng/mL · h^?1 for the test formulation and 40,554 (17,027) ng/mL · h^?1 for the reference formulation. The mean of Cmax for the test formulation was 2472 (933) ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the reference formulation was 2566 (963) ng/mL, and the mean T_max was 3.63 (1.20) hours. The point estimates (90% CIs) for the test/reference ratios of the log-transformed AUC- and C_max mean values were 0.95 (0.87–1.03) and 0.97 (0.89–1.05), respectively, which met the regulatory criteria for bioequiv-alence. Thirty-four mild to moderate adverse events were reported (13 with the test formulation and 21 with the reference formulation), and no serious or unexpected adverse events were observed during the study. The adverse events included 16 cases of headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of diarrhea.Conclusions: The results of this study suggest that the test formulation of imatinib met the regulatory criteria for bioequivalence to the reference formulation in these healthy fasting male volunteers. Both formulations were generally well tolerated and appeared to have a similar adverse-event profile.     

Bioequivalence and pharmacokinetic comparison of a single 200-mg dose of meclofenoxate hydrochloride capsule and tablet formulations in healthy Chinese adult male volunteers: a randomized sequence, open-label, two-period crossover study

BACKGROUND: Meclofenoxate hydrochloride is a psychostimulant in the nootropic agent group available in capsule and tablet formulations approved for traumatic cataphora, alcoholic poisoning, anoxia neonatorum, and children's enuresis in China. Although these 2 generic formulations are marketed in China, information regarding their pharmacokinetics and bioequivalence in humans has not been published. OBJECTIVE: The aim of this study was to compare the pharmacokinetic properties and bioequivalence of the capsule (test) and tablet (reference) formulations of meclofenoxate hydrochloride 200 mg in healthy Chinese volunteers. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. As a prodrug, meclofenoxate is hydrolyzed into 4-chlorophenoxyacetic acid and is not detected in plasma. The active metabolite of meclofenoxate, chlorophenoxyacetic acid, was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity, blood samples were obtained at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 14, and 24 hours after administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Subjects were interviewed concerning the occurrence of adverse events including excitement, insomnia, lassitude, and headache. Tolerability was assessed at baseline (before administration) and at 1, 2, 6, and 12 hours after administration by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis). RESULTS: Twenty-four Chinese male subjects (mean [range]age,23.5[22-30]years;weight,63.3[56-68]kg; height, 171 [165-184] cm) were enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of chlorophenoxyacetic acid Cmax, AUC0-24, and AUC0-infinity were 95.7 to 122.9, 97.6 to 111.9, and 97.8 to 111.7, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No adverse events were reported or observed during this single-dose study. CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 200-mg dose of the capsule formulation was found to be bioequivalent to a single 200-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.     

Relative bioavailability and pharmacokinetics of a new sibutramine formulation in healthy male subjects: a randomized, open-label, two-period, comparative crossover study

BACKGROUND: Sibutramine is an orally administered, centrally acting antiobesity drug. Sibutramine hydrochloride monohydrate is the conventional formulation, whereas sibutramine mesylate hemihydrate is a newly developed formulation. Drugs formed from different salts may differ in their solubility profiles and dissolution rates, which may affect their rate of absorption and thus their onset, duration, and intensity of effect. OBJECTIVE: This study was conducted to compare the relative bioavailability and pharmacokinetics of the new sibutramine formulation (test) with those of the conventional formulation (reference). METHODS:: This was a single-center, randomized, open-label, 2-period, comparative crossover study in healthy male subjects. All subjects received a single 15-mg oral dose of sibutramine hydrochloride monohydrate (reference) and a single 17.3-mg oral dose of sibutramine mesylate hemihydrate (test), both containing 12.55 mg sibutramine base. The 2 doses were separated by a 2-week washout period. Blood samples for pharmacokinetic analysis were collected during a 72-hour period after treatment. Safety parameters were assessed, including adverse events, hematology and biochemistry, urinalysis, and electrocardiography. Plasma concentrations of the active metabolites of sibutramine (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) were determined, and the pharmacokinetic characteristics of the 2 formulations were compared using noncompartmental analysis. RESULTS: Sixteen subjects (mean [SD] age, 24.3 [2.3] years [range, 20-25 years]; mean [SD] body weight, 66.1 [5.1] kg [range, 57-77 kg]) were enrolled in and completed the study. The plasma concentration-time profiles of M1 and M2 were similar after administration of both formulations. The reference and test formulations showed pharmacokinetic equivalence with respect to M1 and M2. The relative bioavailability of the test drug was 117.6% for M1 and 102.4% for M2. The 90% Cls for the ratios of the log-transformed C(max) and AUC values were within the predetermined equivalence range of 80% to 125%. There were no significant changes in physical, biochemical, hematologic, or urinalysis variables during the study. Neither formulation was associated with any serious adverse events. CONCLUSION: In this study in healthy male subjects, the 2 sibutramine formulations were pharmacokinetically equivalent, and the newly developed formulation had a safety profile comparable to that of the conventional formulation.     

Bioequivalence study of two formulations of enalapril, at a single oral dose of 20 mg (tablets): A randomized, two-way, open-label, crossover study in healthy volunteers

Background: Enalapril maleate is the monoethyl ester prodrug of enalapril- at, an angiotensin-converting enzyme inhibitor indicated in the management of essential and renovascular hypertension, and in the treatment of congestive heart failure and in asymptomatic patients with left ventricular dysfunction and an ejection fraction of ≥35%. Enalapril has little pharmacologic activity until hydrolyzed in vivo to enalaprilat.Objective: The aim of the present study was to compare the bioavailability and tolerability of 2 commercial brands (test and reference formulations) of enalapril tablets (20 mg), described as the rate and extent of absorption of the active moiety, to assess their bioequivalence.Methods: This single-dose, randomized, 2-way, open-label, crossover study in healthy volunteers aged 18 to 40 years was conducted at the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos (Madrid, Spain). Subjects were randomized to receive (under fasting conditions) either the test or reference formulation of enalapril (20-mg tablet) at study period 1 and the opposite formulation at study period 2. Study periods were separated by a washout period of at least 7 days. During each study period, 15 plasma extractions were made to determine enalapril and enalaprilat plasma concentrations and to calculate the pharmacokinetic (PK) properties (maximal plasma drug concentration [C_max], time to C_max [T_max], area under the plasma concentration-time curve [AUC] to the last measurable concentration [AUC_t], AUC from time 0 to infinity [AUC_0−∞], mean residence time, and elimination half-life []) of both. Physical examination, subject interview, laboratory analyses, electrocardiogram, and blood pressure (BP) were used to assess tolerability.Results: Twenty-four subjects were included in the study (12 men, 12 women; mean [SD] age, 22.8 [2.2] years [range, 19-30 years]). Of these, 1 subject (4.2%) withdrew from the study for personal reasons; thus, PK and statistical analyses included results from 23 subjects. No statistically significant sequence or period effect was found. T_max was not statistically different between the 2 formulations, and the 90% CI calculated for T_max for the difference of the medians was within the predefined range. The 90% CIs of the logarithmically transformed concentration-derived parameters (C_max AUC_t, and AUC_0−∞) also were within the predefined range; thus, the 2 formulations are considered bioequivalent. For both formulations, systolic and diastolic BPs showed significant reductions compared with baseline values (P < 0.05). Seven adverse effects were recorded, all of them transient and none of severe intensity.Conclusions: In this study of 2 commercial brands (test and reference formulations) of enalapril in healthy subjects, designed and conducted under Good Clinical Practice guidelines, a similar rate and extent of absorption for both formulations were found to be bioequivalent. Both formulations produced a significant decrease in BP values and were generally well tolerated.