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Background HM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions. Objective The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects. Methods A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 µg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay. Results Most of the serum concentrations in the 5 and 15 µg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (Tmax) of HM10460A in the 45, 135, and 350 µg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean ± standard deviation values of the dose-normalized maximum concentration (Cmax) and dose-normalized area under the concentration-time curve (AUClast) for the 45, 135, and 350 µg/kg dosing groups were 14.13 ± 6.37, 66.19 ± 38.71, and 34.65 ± 19.69 µg/ L/mg, respectively, and 265.0 ± 124.1, 2144 ± 1232, and 1386 ± 701.2 µg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEClast) of both the absolute neutrophil count (ANC) and the CD34+ cell count increased as the dose increased. Conclusion HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34+ cell counts. [ABSTRACT FROM AUTHOR]

Background Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix®) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX®), has recently been developed. Objective This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and toler-ability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects. Methods This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study. Results The clopidogrel plasma concentration-time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUClast) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (Imax) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the Imax and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles. Conclusion This study demonstrated that the pharmacoki-netic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects. [ABSTRACT FROM AUTHOR]

Objective: HD203 is a biosimilar of etanercept, a fusion protein of the ligand-binding portion of the human tumor necrosis factor receptor II linked to the Fc portion of human immunoglobulin Gl. Since HD203 is under clinical development, this study was conducted to compare the pharmacokinetics of HD203 with Enbrel®, the first marketed etanercept. Methods: A double-blind, randomized, single-dose, two-period, two-sequence, crossover study was conducted in 37 healthy volunteers. In each period, 25mg/mL of reconstituted lyophilized reference (Enbrel®) or test product (HD203) was administered subcutaneously, either the reference product followed by the test product, or vice versa. Serial blood samples for pharmacokinetic analysis were taken for 480 hours after dosing, and serum concentrations of the products were determined using a commercial enzyme-linked immunosorbent assay. The geometric mean ratios with 90% confidence intervals for the maximum concentration (Cmax) and the area under the concentration-time curve from time 0 to the last measurable time point (AUC0-t) were estimated. Results: A total of 35 subjects completed the study; serious adverse events were not observed. The mean serum concentration-time profiles of the two products were similar. The Cmax and AUC0-t values of the reference product (mean±standard deviation) were 1.25±0.45mg/L and 283.15 ±98.57 mg*h/L, respectively, while those of the test drug were 1.35±0.47mg/L and 315.78 ± 99.38 mg*h/L, respectively. The geometric mean ratios (90% confidence intervals) of the test to the reference for Cmax and AUC0-t were 1.08 (1.00, 1.16) and 1.13 (1.05, 1.21), respectively. Conclusions: A single subcutaneous injection of HD203 or Enbrel® into healthy volunteers appeared to be safe and well tolerated. Comparative pharmacokinetics demonstrated that reconstituted lyophilized HD203 has bioavailability similar to that of Enbrel®. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. Methods. A single 5-mg capsule of tropisetron was administered orally to 13 healthy subjects. Plasma concentrations were determined by validated HPLC procedures and data were analyzed by using noncompartmental linear PK methods. Four alleles, CYP2D6*1, CYP2D6*2 ×2, CYP2D6*5, and CYP2D6*10, were identified by PCR. Results. Thirteen subjects, consisting of two homozygous carriers of the wild type allele (*1/*1), four heterozygous carriers of poor metabolizer (PM)-associated allele (*1/*10), six homozygous carriers of PM-associated alleles (four with *10/*10 and two with *5/*10), and one carrier of a duplicated allele *1/*2 ×2. All tested pharmacokinetic parameters (AUCinf, AUCinfNL70, Cmax, CmaxNL70, T1/2, and Tec) were significantly different among four different genotypic groups. The mean AUCs of carriers with the heterozygous PM-associated allele and the homozygous PM-associated allele were 1.9- and 6.8-higher than those of carriers with the wild type allele, respectively. In contrast, the mean AUC of carriers with a duplicated allele was 0.5-fold lower than that of those carriers with the wild type allele. Conclusion. The presence of CYP2D6*5, CYP2D6*10, and CYP2D6*2 ×2 has an important impact on the pharmacokinetics of tropisetron, which may influence clinical response to tropisetron therapy. [ABSTRACT FROM AUTHOR]