Safety and immunogenicity of a single intramuscular dose of a tetanus-diphtheria toxoid (Td) vaccine (BR-TD-1001) in healthy Korean adult subjects.

BR-TD-1001 was developed as a booster for the immunity maintenance of diphtheria and tetanus. The aim of this study was to evaluate the safety and immunogenicity of BR-TD-1001 (test vaccine) in comparison with placebo and an active comparator in healthy Korean adults. A randomized, double-blind, placebo-controlled, active comparator, phase I clinical trial was conducted. Fifty subjects were randomly assigned to one of 3 treatment groups in a ratio of 2:2:1, and were administered a single intramuscular dose of test vaccine, active comparator, or placebo, respectively. All subjects were monitored for 4 weeks after injection. The antibody titers of the patients 2 and 4 weeks after vaccination were compared with the baseline. The frequencies of all adverse events including adverse drug reactions in the test group were not statistically different from those of the other treatment groups (P = 0.4974, 0.3061). No serious adverse event occurred, and no subject was withdrawn from the study for safety. The seroprotection rates against both tetanus and diphtheria at 4 weeks after vaccination were over 0.95. For anti-tetanus antibody, the geometric mean titer in the test group was significantly higher than those of the other groups (P = 0.0364, 0.0033). The geometric mean titer of anti-diphtheria antibody in the test group was significantly higher than the value of the placebo (P = 0.0347) while it was not for the value of the active comparator (P = 0.8484). In conclusion, BR-TD-1001 was safe, well-tolerated, and showed sufficient immunogenicity as a booster for diphtheria and tetanus.

Assessment of the analgesic effect of remifentanil using three pain models in healthy Korean volunteers: a randomized, controlled study.

Quantitative pain assessment in human beings is useful for developing new analgesics. This study assessed the analgesic effect of remifentanil in 20 healthy Korean men using three pain models to investigate whether these models can be used in Asians. The study was a double-blind, placebo-controlled, two-way cross-over study. The subjects received intravenous remifentanil with doses starting at 0.01 µg/kg/min. and increasing by 0.01 µg/kg/min. up to 0.10 µg/kg/min. in one session; they received placebo in another session. Heat pain thresholds were assessed at dose levels of 0.02, 0.05, 0.08 and 0.10 µg/kg/min. Pressure pain threshold and tolerance and mechanical pain threshold were assessed at 0.08 µg/kg/min. Remifentanil dose-dependently increased the heat pain threshold. The differences (95% confidence interval) between remifentanil and placebo were 1.54°C (0.78, 2.31), 1.82°C (1.11, 2.54) and 2.47°C (1.55, 3.38) at 0.05, 0.08 and 0.10 µg/kg/min. remifentanil, respectively. Remifentanil conferred a significantly higher pressure pain threshold and tolerance than placebo (p = 0.0001). There was a trend of increasing mechanical pain threshold with remifentanil, although it was not statistically significant. The results suggest that heat pain and pressure pain models are valid in East Asians for assessing analgesic effects.

Pharmacokinetics of extended-release versus conventional tramadol/acetaminophen fixed-dose combination tablets: an open-label, 2-treatment, multiple-dose, randomized-sequence crossover study in healthy korean male volunteers.

BACKGROUND: A fixed-dose combination tablet of tramadol/acetaminophen exhibits both rapid and sustained analgesic effects due to different pharmacologic activities. To prolong analgesia and improve patient convenience, an extended-release (ER) tablet of this agent has been developed. OBJECTIVE: The aim of this study was to explore the pharmacokinetic profiles of the new ER tramadol/acetaminophen fixed-dose combination and compare them with those of a conventional immediate-release (IR) formulation after multiple dosing as a Phase I clinical exploratory trial. METHODS: An open-label, randomized, 2-sequence crossover study was conducted in healthy volunteers. All subjects received both formulations for 4 days: either 1 IR tablet (tramadol 37.5 mg/acetaminophen 325 mg) q6h followed by 1 ER tablet (tramadol 75 mg/acetaminophen 650 mg) q12h, or vice versa. A 5-day washout period separated the 2 treatments. Tramadol and acetaminophen concentrations in plasma were determined simultaneously using LC-MS/MS, and the pharmacokinetic properties were analyzed by noncompartmental method. To compare the systemic exposure of the 2 formulations, the geometric mean ratios (GMRs) for AUC(0-12,ss) and the 90% CIs were calculated. Adverse events (AEs) were identified through subject interviews, recording of vital signs, physical examinations, 12-lead electrocardiography, and clinical laboratory assessments. RESULTS: Twelve healthy, nonsmoking, Korean male subjects completed the study. The mean (SD) age was 24.4 (5.2) years and the mean body weight was 65.1 (6.0) kg. The T(max,ss) for tramadol was delayed until 3 hours after the ER treatment, compared with 1 hour after the IR treatment, whereas the T(max,ss) of acetaminophen was 30 minutes after each treatment. The mean (SD) of AUC(0-12,ss) in the IR and ER formulations was 2789.0 (507.7) and 2638.7 (469.1) µg/h/L for tramadol and 42,635.0 (8711.2) and 40,394.3 (10,127.7) µg/h/L for acetaminophen, respectively. The GMR of ER to IR for AUC(0-12,ss) was 0.95 (90% CI, 0.91-0.99) for tramadol and 0.94 (90% CI, 0.89-0.99) for acetaminophen. A total of 17 AEs occurred in 9 subjects; all AEs were considered mild or moderate and resolved without medical intervention. The most frequent AEs were headache and dizziness (3 cases each). CONCLUSIONS: The ER formulation displayed a similar AUC(0-12,ss) to that of the IR formulation for tramadol and acetaminophen.

Effect of ketoconazole on the pharmacokinetics of udenafil in healthy Korean subjects.

AIMS: Udenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction. It is metabolized to DA-8164, a major metabolite, by CYP3A4. This study was performed to investigate the effect of ketoconazole, a known CYP3A4 inhibitor, on the pharmacokinetics of udenafil. METHODS: An open-label, two-period, fixed-sequence crossover study was performed in 12 healthy male volunteers. They received a single 100-mg oral dose of udenafil. Following a 5-day interval, 400 mg of ketoconazole was administered once a day for three consecutive days. On day 3 of ketoconazole treatment, a second 100 mg of udenafil was dosed concomitantly. Blood samples were collected at time points up to 48 h without ketoconazole treatment and up to 72 h with ketoconazole co-administration. The plasma concentration of udenafil was determined using liquid chromatography-tandem mass spectrometry. RESULTS: Following ketoconazole co-administration, the mean C(max) and AUC(last) of udenafil (95% confidence interval) increased 1.9-fold (1.60, 2.27) and 3.2-fold (2.82, 3.63), respectively. The median time to reach the C(max) was delayed in the co-administrated treatment, while the mean terminal elimination half-life (t(1/2)) remained relatively unchanged regardless of ketoconazole co-administration. The metabolic AUC ratio (AUC(last) of DA-8164/AUC(last) of udenafil) was 1.71 when udenafil was administered alone, and the value decreased to 0.19 when udenafil was dosed in the presence of ketoconazole. Regarding safety assessments, no clinically significant difference or serious adverse event was observed. CONCLUSIONS: The systemic exposure of udenafil increased significantly when it was administered with ketoconazole. Dose adjustment may be required when these drugs are used together.

Comparative pharmacokinetic evaluation of two formulations of bicalutamide 50-mg tablets: an open-label, randomized-sequence, single-dose, two-period crossover study in healthy Korean male volunteers.

BACKGROUND: Bicalutamide is an oral nonsteroidal antiandrogen drug used during hormone ablation therapy for prostate cancer. A new generic formulation of bicalutamide has been developed. OBJECTIVES: This study was conducted to meet Korean and US regulatory requirements for the marketing of the generic 50-mg tablet formulation of bicalutamide. To this end, the pharmacokinetic properties of the new (test) formulation were compared with those of the currently marketed (reference) formulation. Tolerability was also evaluated. METHODS: An open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy Korean male volunteers. Subjects received either the test or reference formulation of bicalutamide 50-mg tablets in the first period and crossed over to the alternative formulation in the second period. Serial blood samples for pharmacokinetic analysis were taken over 672 hours after dosing. Plasma concentrations of bicalutamide were measured by HPLC-MS/MS. Pharmacokinetic parameters, including AUC(0-672h), were determined by noncompartmental analysis. Log-transformed C(max) and AUC(0-672h) for the 2 formulations were compared. Tolerability was monitored based on laboratory tests, ECGs, vital signs, and physical examinations. RESULTS: Of the 34 subjects initially enrolled, 33 completed the study. The mean (SD) age, height, and weight of participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The median T(max) was 36.0 hours for both formulations. The mean (SD) t(1/2), C(max), and AUC(0-672h) for the reference formulation were 135.4 (28.6) hours, 933.2 (169.2) microg/L, and 215,680.1 (48,753.4) microg x h/L, respectively. Corresponding values for the test formulation were 134.3 (30.7) hours, 946.7 (179.9) microg/L, and 221,708.8 (54,935.1) microg x h/L. The 90% CIs for the mean ratios (test/reference) of log-transformed C(max) and AUC(0-672h) were 0.97 to 1.06 and 0.98 to 1.07, respectively. Twelve adverse events were reported for each formulation, none of which were considered drug related in the test-formulation group and 4 of which were considered drug related in the reference-formulation group (3 cases of headache, 1 case of erythematous rash). CONCLUSIONS: In this single-dose study in healthy Korean male subjects, the new formulation of bicalutamide 50-mg tablets met Korean and US regulatory criteria for assumption of bioequivalence with the currently marketed formulation. Both formulations were generally well tolerated, with no clinically relevant safety concerns.