Jeong Ju Seo

Effect of age on the pharmacokinetics of fimasartan (BR-A-657)

Objectives: The aim of this study was to compare the pharmacokinetics (PK) and safety of fimasartan (BR-A-657), an angiotensin II receptor antagonist, between healthy young (19 – 45 years) and older (≥ 65 years) male subjects. Methods: To assess the effect of age on PK and safety, fimasartan was administered as a single 240 mg tablet to 12 young and 10 older male subjects, followed by serial blood sampling over 48 h. Plasma concentrations of fimasartan were analyzed using validated HPLC-MS/MS. Clinical and laboratory adverse events were assessed. Results: After oral administration of 240 mg fimasartan, the mean area under the plasma concentration-time curve from time zero to infinity (AUC0→∞) was 2899.0 ng/ml/h in the older, which was significantly greater than in young subjects (1767.4 ng/ml/h; p = 0.03). The geometric mean AUC0→∞ was 69.4% higher in older than in young subjects. The maximum plasma concentration (Cmax), time to reach Cmax and elimination half-life for fimasartan did not differ significantly between the older and young groups. Importantly, fimasartan was well tolerated during this study. Conclusions: While some PK parameters were statistically different between the two groups, the effect of age on the PK was modest (e.g., AUC increase < twofold in older subjects).

Rapid determination of sumatriptan in human plasma by ultra performance liquid chromatography–tandem mass spectrometry and its application to clinical pharmacokinetic study

A sensitive and simple detection method coupling ultra-performance liquid chromatography with tandem mass spectrometry was developed and validated to analyze sumatriptan levels in human plasma. The plasma sample preparations for the analysis were based on liquid-liquid extraction with ethyl acetate, evaporation, and reconstitution. MS/MS detection was performed on a triple-quadrupole tandem mass spectrometer by monitoring the protonated parent→daughter ion pairs at m/z 296→58 and m/z 388→71 for sumatriptan and terazosin (internal standard), respectively. The method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear from 0.5 to 50 ng/mL (r>0.999). The mean extraction recovery for sumatriptan was higher than 62.3%. The method accuracy was within 97.4%, and the relative standard deviation of the intra- and inter-day precision values was within 11.7% at all quality control levels. Plasma samples that contained sumatriptan were stable under three freeze-thaw cycles, short- and long-term storage, and autosampler conditions. This method was successfully applied to a pharmacokinetic study conducted with 10 healthy volunteers. After oral administration of 50-mg sumatriptan and serial blood sampling over 12 h, the mean area under the plasma concentration-time curve from time 0 to 12 h and the maximum plasma concentration were 116.2 ng h/mL and 33.2 ng/mL, respectively.

Non-cross-bridged tetraazamacrocyclic chelator for stable (64)cu-based radiopharmaceuticals.

N-mono/dimethylated TE2A tetraazamacrocycles (MM-TE2A and DM-TE2A) were synthesized in high yields. Both Cu-MM/DM-TE2A complexes showed increased kinetic stability compared to that of Cu-TE2A, whereas Cu-DM-TE2A showed even higher in vitro stability than that of Cu-ECB-TE2A. MM-TE2A and DM-TE2A were quantitatively radiolabeled with (64)Cu ions and showed rapid clearance from the body to emerge as a potential efficient bifunctional chelator.

Single-dose pharmacokinetics and dose proportionality of intravenous pazufloxacin mesilate in healthy Korean volunteers

Objective: The aim of this study was to investigate the pharmacokinetics and dose proportionality of a single, intravenous dose of pazufloxacin mesilate, an injectable fluoroquinolone antibiotic, in healthy Korean male volunteers. Methods: In this open-label, four-dose, parallel study, subjects were randomized to receive a single dose of pazufloxacin mesilate 300, 500, 600, and 1,000 mg (n = 6, 20, 6, and 8, respectively) administered as a 1-h intravenous infusion. Blood and urine samples were collected serially from 0 to 24 h after drug administration and analyzed using a validated HPLC method. Tolerability was assessed by monitoring clinical laboratory parameters and adverse events. Results: After single-dose intravenous administration of pazufloxacin mesilate, the mean Cmax for groups treated with 300, 500, 600, and 1,000 mg doses ranged from 5.11 to 18.06 μg/mL; the mean AUC0-t ranged from 13.70 to 58.60 μg × h/mL. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 – 1,000 mg, based on linear regression model and power model. At all four dosages studied, pazufloxacin mesilate was well tolerated. Conclusions: Our data suggest that all regimens of pazufloxacin administration were well tolerated. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 – 1,000 mg.

A Phase I study to characterize the multiple-dose pharmacokinetics, pharmacodynamics and safety of new enteric-coated triflusal formulations in healthy male volunteers

Objectives: An enteric-coated formulation of triflusal (triflusal EC), an antiplatelet agent, was developed to reduce the high incidence of gastrointestinal adverse events (AEs). The aim of this study is to compare the pharmacokinetics, pharmacodynamics and safety of triflusal EC with triflusal in healthy Korean male subjects to determine bioequivalence and non-inferiority for the purposes of marketing approval. Methods: A randomized, open-label, two-period, crossover study was conducted in 38 subjects. Either triflusal EC or triflusal was administered orally as a single 900 mg loading dose (day 1) followed by eight 600 mg/day maintenance doses on days 2 – 9, with a 13-day washout period. The plasma concentrations of 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), the predominant active metabolite of triflusal, were assessed after administration of the loading dose, using HPLC/MS/MS. The platelet aggregation response to arachidonic acid was determined using turbidimetric aggregometry. Results: The 90% CIs, for the geometric mean ratios of the log-transformed AUCτ and Cmax of HTB were seen to be within the predetermined range of 0.8 – 1.25. Triflusal EC was also shown to be non-inferior in its anti-aggregatory effect. No serious AEs were reported during this study. Conclusions: The pharmacokinetic and pharmacodynamic profiles of the two triflusal formulations met the requirements for bioequivalence and non-inferiority, respectively. Both formulations were well tolerated.

Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography–mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5′-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.

Assessment of pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers

Objective: Levofloxacin and cyclosporine show different pharmacokinetic properties, but are known to be dose proportional within the therapeutic range. The authors evaluated the pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methods: Two independent, randomized, crossover studies were performed. For levofloxacin, eight volunteers were randomly assigned in a 1:1 ratio to receive a low dose (7.5 mg) orally or intravenously, followed by a 1-week washout period and administration via the alternate route. After another 1-week washout period, a therapeutic dose (750 mg) was administered to all eight subjects. For cyclosporine, another eight volunteers received a low dose (2 mg) or a therapeutic dose (200 mg) orally with a 1-week washout period. Drug concentrations were determined by LC-MS/MS. Results: For levofloxacin, the mean values for dose-normalized Cmax and AUClast with the two doses were as follows: therapeutic dose, 15.2 ± 4.6 ng/ml/mg and 103.6 ± 15.5 ng·h/ml/mg, respectively; low dose, 17.1 ± 6.5 ng/ml/mg and 72.6 ± 8.7 ng·h/ml/mg, respectively. For cyclosporine, the mean values for dose-normalized Cmax and AUClast were as follows: therapeutic dose, 4.9 ± 1.5 ng/ml/mg and 15.4 ± 4.9 ng·h/ml/mg, respectively; low dose, 1.6 ± 0.6 ng/ml/mg and 9.3 ± 7.3 ng·h/ml/mg, respectively. Conclusion: In this study levofloxacin, which is completely absorbed and primarily eliminated renally without modification, showed better pharmacokinetic proportionality than cyclosporine, which is poorly absorbed and extensively metabolized.

Clinical evaluation of efficacy and tolerability of HMC05 in healthy subjects with normal and high-normal blood pressure: a pilot study.

HMC05, a formulation containing eight different herbal extracts, has been used widely for several thousand years in China, Japan, and Korea as a remedy for hypertension and headache. Although its anti-inflammatory effects in mouse monocytic cell lines and anti-atherosclerotic effects in apoE-knockout mice have been reported, the pharmacodynamic effects of HMC05 in human subjects have not yet been investigated. We evaluated the efficacy and tolerability of this drug in 14 healthy male Korean subjects with normal or high-normal blood pressure (BP) in a randomized, single-blind, crossover study with a 2-week washout period. Four 500-mg tablets of HMC05 or placebo were orally administered three times daily to nine subjects with normal BP and five subjects with high-normal BP for 4 weeks. To assess the pharmacodynamic effects of HMC05, levels of high-sensitivity C-reactive protein and homocysteine, BP, and flow-mediated vasodilation were measured before and after the 4-week medication period with evaluation of tolerability. All 14 subjects completed the study, and HMC05 was well tolerated with no significant adverse events. HMC05 did not exhibit a significant BP-lowering effect in either BP group, and there were no significant differences in other pharmacodynamic values after HMC05 or placebo administration in the two groups. Further study is needed to evaluate the efficacy and tolerability of HMC05 in an adequate number of patients with hypertension.