Search

Jung Sunwoo,1 Yu Kyong Kim,1 Yewon Choi,1 Kyung-Sang Yu,1 Heesook Nam,2 Young Lag Cho,2 Seonghae Yoon,3 Jae-Yong Chung3 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2LegoChem Biosciences, Inc., Daejeon, 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea Background: LCB01-0371 is a novel oxazolidinone antibiotic that blocks protein production by binding to bacterial 23S ribosomes. This antibiotic is active against Gram-positive bacteria. This study aimed to evaluate the effect of food on the pharmacokinetics (PKs) of LCB01-0371 and evaluate its safety profile.Subjects and methods: A randomized, open-label, two-way crossover study was performed in 18 healthy Korean male subjects. All subjects received a single oral 800mg dose of LCB01-0371 in each period under fed or fasting condition with a 7-day washout in between. The fed condition was defined as consumption of a meal of 800–1,000kcal containing ~50% of fat content. Serial blood samples were collected over 24h after dosing, and the PK parameters were calculated by noncompartment analysis. All available data of the subjects who received LCB01-0371 at least once were included in the safety data summaries.Results: In the fed condition, both the maximum plasma concentration (Cmax) and the total systemic exposure (area under the plasma concentration–time curve from time zero to the last observed time point [AUClast]) decreased by ~33% and 10%, respectively. The time to reach Cmax was delayed by ~1.25h in the fed condition, whereas the mean elimination half-life remained similar in both conditions. In the fed/fasting condition, the geometric mean ratios and 90% CI of the Cmax and AUClast were 0.666 (0.470–0.945) and 0.897 (0.761–1.057), respectively. There were no drug-related adverse events (AEs) or serious AEs.Conclusion: Although the Tmax after a single oral 800mg dose of LCB01-0371 was slightly delayed under the fed condition compared to the fasting condition, the total systemic exposure was similar under both conditions. Therefore, LCB01-0371 could be administered regardless of food intake. Keywords: antibiotic resistance, gram-positive bacteria, clinical trial

Yewon Choi,1 Seonghae Yoon,1 Kyoko Matsumoto,2 Yoshiyasu Ohta,3 SeungHwan Lee,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Ikuyaku Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan; 3Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan Introduction: Telaprevir, a reversible selective inhibitor of viral protease and a potential blocker of viral replication, is indicated for the treatment of hepatitis C virus genotype 1 infection. In this study, the pharmacokinetic profile, safety, and tolerability of telaprevir and the effect of food on telaprevir exposure were evaluated in healthy Korean subjects, and compared with data from a previous study in Japanese male subjects. Methods: The single ascending dose study was conducted in 3 dose-based groups (500, 750, and 1,250 mg, six subjects each) in a fasted state. In the multiple dose study, eight subjects in the fed state received 750 mg of telaprevir once on Day 1 and every 8 hours from Day 2 until the morning of Day 6. Serial blood samples for pharmacokinetic analysis were collected for up to 24 hours in the single ascending dose study and for 6 days in the multiple dose study. Individual pharmacokinetic parameters were calculated using a non-compartmental analysis method. Safety and tolerability profiles were evaluated throughout the study. Results: Following multiple administrations of telaprevir, maximum plasma concentrations (Cmax), area under the concentration–time curve (AUC0–8), and Ctrough (concentration at 8 h after drug administration) increased by ~2.41-fold. Compared to fasted state values, mean Cmax and AUC0–24 increased by 4.92- and 4.81-fold, respectively, after food intake. The Cmax and AUCinf of Korean subjects were 26%–34% higher than those of Japanese subjects; however, these differences were not clinically significant. All observed adverse events were mild and there was no discontinuation due to AEs. Conclusion: In conclusion, the telaprevir’s pharmacokinetic characteristics were similar in Korean and Japanese subjects. Telaprevir was well tolerated in a single dose of up to 1,250 mg and in multiple doses of 750 mg. Keywords: antiviral agents, hepatitis C virus, NS3/4A protease, ethnicity, pharmacokinetic profile

Jieon Lee,1 Seonghae Yoon,1 Donghoon Shin,1 HyeKyung Han,1 Hyungmi An,1,2 Jongtae Lee,1 Kyoung Soo Lim,3 Kyung-Sang Yu,1 Howard Lee11Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea; 2Department of Statistics, College of Natural Sciences, Seoul National University, Seoul, Korea; 3Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, KoreaBackground: Several nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients.Methods: Gentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with "other" infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated.Results: Gentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%–72.3% vs 4.3%–45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients.Conclusion: Gentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.Keywords: antibiotics, infectious endocarditis, therapeutic drug monitoring, Bayesian method

Seonghae Yoon,1 Donghoon Shin,1 Howard Lee,1,2 In-Jin Jang,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul National University Hospital, 2Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea Introduction: LC350189 is a novel selective xanthine oxidase inhibitor under clinical development for the management of hyperuricemia in gout patients. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of the drug in healthy subjects. Methods: A dose-block randomized, double-blind, active and placebo-controlled, single- and multiple-dosing study was conducted. A single ascending dose (SAD) study (10–600mg) and a multiple ascending dose (MAD) study with once-daily doses (100–800mg) for 7days were conducted. Serial samples of blood and urine for pharmacokinetics/pharmacodynamics analysis were collected, and tolerability and adverse events were assessed throughout the study. Results: Sixty-seven and 58 subjects were enrolled in the SAD and MAD studies, respectively. The mean Cmax and AUClast values increased with increasing doses, and exposure to LC350189 was dose proportional. The 24-hour mean serum uric acid (Cmean,24) decreased by 8.7%–31.7% (day 1) and 53.5%–91.2% (day 7) from baseline in the SAD and MAD studies, respectively, and the percentage decrease in Cmean,24 increased with higher doses. Conclusion: LC350189 was well tolerated in the dose range of 10–800mg. It lowered the serum and urine uric acid levels substantially in this dose range; the extent of the decrease in the serum uric acid level in the 200mg dose group was similar or higher compared to that of febuxostat 80mg group in the MAD study. It is expected that LC350189 could be safely administered once daily to patients with hyperuricemia or gout, leading to a sufficient decrease in uric acid levels. Keywords: gout, xanthine oxidase inhibitor, pharmacokinetics, pharmacodynamics, LC350189&nbsp

Kyungho Jang, Seonghae Yoon, Sung-Eun Kim, Joo-Youn Cho, Seo Hyun Yoon, Kyoung Soo Lim, Kyung-Sang Yu, In-Jin Jang, Howard LeeDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of KoreaBackground: Megestrol acetate is an effective treatment for improving appetite and increasing body weight in patients with cancer-associated anorexia. However, Megace® oral suspension (OS), a micronized formulation of megestrol acetate, has low bioavailability in the fasting state. To overcome this limitation, a nanocrystal formulation has been developed. This study was performed to evaluate the pharmacokinetics and tolerability of the nanocrystal formulation and to compare them with those of Megace® OS in the fed and fasting states.Methods: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in three parts in 93 healthy subjects. A single 625 mg/5 mL oral dose of a nanocrystal formulation was administered in the fasting and fed states (part I). In parts II and III, a single 625 mg/5 mL oral dose of the nanocrystal formulation or Megace® OS 800 mg/20 mL was given in the fed and fasting states, respectively. Blood samples were collected for up to 120 hours post dose for pharmacokinetic analysis. Tolerability was evaluated throughout the entire study period.Results: The nanocrystal formulation of megestrol acetate was rapidly absorbed in both the fed and fasting states. In the fed state, systemic exposure was comparable between the nanocrystal formulation of megestrol acetate and Megace® OS. In the fasting state, however, the peak plasma concentration and area under the plasma concentration-time curve to the last measurable concentration of megestrol acetate was 6.7-fold and 1.9-fold higher, respectively, for the nanocrystal formulation than for Megace® OS. No serious adverse events were reported.Conclusion: Systemic exposure to megestrol acetate is less affected by lack of concomitant food intake when it is administered using the nanocrystal formulation. The nanocrystal formulation of megestrol acetate could be more effective in treating patients with cachexia or anorexia.Keywords: megestrol acetate, nanocrystal formulation, food, anorexia

Seonghae Yoon,1,* Howard Lee,2,* Tae-Eun Kim,1 SeungHwan Lee,1 Dong-Hyun Chee,3 Joo-Youn Cho,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Clinical Trials Center, Seoul National University Hospital, 3AbbVie Ltd., Seoul, Republic of Korea *These authors contributed equally to this work Background: This study was conducted to compare the oral bioavailability of an itopride extended-release (ER) formulation with that of the reference immediate-release (IR) formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. Methods: A single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22–48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax) and area under the plasma concentration versus time curve over 24 hours after dosing (AUC0–24h), were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. Results: A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC0–24h were contained within the conventional bioequivalence range of 0.80–1.25 (0.94 [0.88–1.01]), although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC0–24h was not affected. There were no serious adverse events and both formulations were generally well tolerated. Conclusion: At steady state, once-daily itopride ER at 150 mg has a bioavailability comparable with that of itopride IR at 50 mg given three times a day under fasting conditions. Food delayed the absorption of itopride ER, with no marked change in its oral bioavailability. Keywords: itopride, extended-release, immediate-release, bioavailability, pharmacokinetics