Comparative bioavailability of two tablet formulations of emtricitabine/tenofovir in healthy, fasting volunteers: a single-dose, randomized-sequence, open-label crossover study.

OBJECTIVE: To evaluate the relative bioavailability of a new formulation of emtricitabine (EMT) 200 mg and tenofovir disoproxil fumarate (TNF) 300 mg and to compare with reference formulation to meet regulatory criteria in Argentina. METHODS: A randomized-sequence, open-label, twoperiod crossover study was conducted on 24 healthy Caucasian volunteers in a fasting state. A single oral dose of T or R formulations was followed by a 7-day washout period. Samples were collected at baseline, 0.25, 0.50, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 7, 12, 24, and 48 hours after administration. EMT and TNF were determined by LC-MS/MS. RESULTS: Geometric means (90% CI) Cmax for EMT in test and reference were 1,891.22 (1,777.1 - 2,187.31) and 1,830.31 (1,721.19 - 2,134.01) ng/mL, the AUC0-t were 10,283.07 (9,624.29 - 11,566.34) and 10,518.76 (9,942.79 - 11,578.30) ng × h/mL and the AUC0-∞ were 10,615.14 (9,948.56 - 11,866.26) and 10,804.12 (10,221.04 - 11,864.85) ng × h/mL, respectively. For TNF test and reference, Cmax geometric means (CI range) were 202.91 (187.91 - 255.78) and 212.04 (195.98 - 264.87) ng/mL, AUC0-t were 1,429.96 (1,334.63 - 1,680.00) and 1,420.75 (1,326.76 - 1,622.18) ng × h/mL and AUC0-∞ were 1,657.11 (1,551.60 - 1,921.75) and 1,631.84 (1,523.95 - 1,857.97), respectively. No differences were detected between the formulations. The test/reference ratios (90% CI) for Cmax, AUC0-t, and AUC0-∞ were 103.33% (95.7 - 111.6), 97.76% (93.6 - 102.1), and 98.25% (94.3 - 102.4) for EMT, and 95.70% (85.9 - 106.6), 95.20% (83.4 - 108.6) and 91.10% (80.7 - 102.7) for TNF. CONCLUSIONS: In this single-dose study, the EMT/TNF tablets (test formulation) met the standard 90% CI criterion for bioequivalence with the reference formulation.

Comparative bioavailability of 2 tablet formulations of levodopa/benserazide in healthy, fasting volunteers: a single-dose, randomized-sequence, open-label crossover study.

BACKGROUND: Currently, levodopa administered with decarboxylase inhibitors is the gold standard for the management of the motor symptoms of Parkinson's disease, a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In Argentina, only 1 commercial product is available with such composition; this study was contracted by the manufacturer to comply with new generic product regulations. OBJECTIVE: The aim of this study was to evaluate the fasting bioavailability of a new generic formulation of levodopa 200 mg/benserazide 50 mg tablets (test) and compare this generic formulation with the branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. METHODS: A randomized-sequence, open-label, 2-period, crossover study was conducted between August and October 2009 in healthy Caucasian volunteers (n = 24; 18 males, aged 21 to 42 years, with a body mass index ranging from 19.7 to 26.0 kg/m(2)) in the fasted state. A single oral dose of the test or reference formulation was administered, and after a 7-day washout period, the other formulation was given. Blood samples were collected at baseline and at 10, 20, 30, 40, 50, 60, 70, 80, 90, and 105 minutes and 2, 2.5, 3, 3.5, 4, and 6 hours after dosing. Levodopa plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection, without stereo-specificity assessment. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test/reference) for the C(max) and AUC(0-t) of levodopa were within the 0.8 to 1.25 range. Adverse events were monitored throughout the study, based on clinical parameters and patient reports. RESULTS: The geometric means (90% CI) of the C(max) for the test and reference formulations were 2462.02 (2312.06-3492.40) and 2542.85 (2394.49-3231.29) ng/mL, respectively; the AUC(0-t) was 3878.04 (3623.88-5393.09) and 3972.10 (3765.88-5393.02) ng/mL/h, respectively; and the AUC(0-∞)was 4610.37 (4315.71-6315.70) and 4728.96 (4502.17-6828.26) ng/mL/h, respectively. There were no significant differences in pharmacokinetic parameters between the 2 formulations. The test:reference ratios for C(max), AUC(0-t), and AUC(0-∞) were 96.82% (90% CI, 83.87-111.77), 97.63% (90% CI, 85.95-110.91), and 97.49% (90% CI, 84.09-113.02), respectively. No clinically significant adverse events were reported; this finding is probably the result of subjects not believing that their side effects were severe enough to be reported and not because of a genuine and absolute lack of predictable side effects. CONCLUSIONS: In this single-dose study, the test formulation of levodopa/benserazide tablets met the Argentinean criterion for bioequivalence to the reference formulation. (www.clinicaltrials.gov: NCT01327261).

Immunogenicity and reactogenicity of a combined fully liquid DTPw-HepB-Hib pentavalent vaccine in healthy infants: no clinically relevant impact of a birth dose of hepatitis B vaccine.

OBJECTIVES: In this open-label, non-randomized phase II study, the safety and immunogenicity of a fully liquid diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HepB-Hib) combination vaccine (Quinvaxem(®)) were assessed in infants who had or had not received a birth dose of hepatitis B (HepB) vaccine. STUDY DESIGN: Two groups of infants, 'HepB at birth' (n=110) and 'no HepB at birth' (n=108), were enrolled and received a primary vaccination course using a 2-4-6 months schedule. RESULTS: Seroprotection/seroconversion rates of >95% were achieved against all antigens included in the combination vaccine for both study groups. Although significantly higher anti-hepatitis B virus (p<0.001) and anti-tetanus (p=0.031) antibody titers were achieved in group 'HepB at birth' when compared with group 'no HepB at birth', the proportion of 'no HepB at birth' subjects achieving protective titers was non-inferior to the proportion of subjects in group 'HepB at birth'. The birth dose of HepB vaccine did not seem to influence the safety pattern of the DTPw-HepB-Hib combination vaccine. CONCLUSIONS: The present study demonstrated that the fully liquid DTPw-HepB-Hib vaccine was safe and immunogenic when administered using a 2-4-6 months immunization schedule, regardless of whether or not infants had received a dose of HepB vaccine at birth.

Bioequivalence of two tablet formulations of clopidogrel in healthy Argentinian volunteers: a single-dose, randomized-sequence, open-label crossover study.

BACKGROUND: Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Thienopyridines, particularly clopidogrel, are highly effective in reducing in-stent thrombosis and functional inhibition of adenosine diphosphate-induced platelet activation. OBJECTIVE: The aim of this study was to evaluate the bioequivalence of a new generic formulation of clopidogrel 75-mg tablets (test) and the available branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. METHODS: This was a randomized-sequence, open-label, 2-period crossover study conducted in healthy white volunteers in the fasted state. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. Clopidogrel concentrations were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test:reference) for C(max) and AUC(0-last) were within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports. RESULTS: Twenty-four volunteers (13 male, 11 female; mean [SD] age, 33.7 [5.2] years [range, 21-42 years]; weight, 72.4 [6.83] kg [range, 59-82 kg]) were enrolled in and completed the study. The geometric mean C(max) for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC(0-t) was 1911.53 and 2053.09 pg . h/mL, and the geometric mean AUC(0-infinity)) was 2021.33 and 2188.25 pg . h/mL. The geometric mean ratios (test:reference) for C(max), AUC(0-t), and AUC(0-infinity)) were 96.09% (90% CI, 90.71-101.78), 93.10% (90% CI, 85.57-101.3), and 92.37% (90% CI, 85.06-100.31), respectively. There were no significant differences in pharmacokinetic parameters between groups. No adverse events were reported. CONCLUSION: In this single-dose study in healthy fasted volunteers, the test formulation of clopidogrel tablets met the US and Argentinian regulatory criterion for bioequivalence to the reference formulation.