C o p y r i g h t © 2 0 1 3 I n f o r m a U K L i m i t e d N o t f o r S a l e o r C o m m e r c i a l D i s t r i b u t i o n U n a u t h o r i z e d u s e p r o h i b i t e d . A u t h o r i s e d u s e r s c a n d o w n l o a d , Abstract Objectives:Zabofloxacin is being developed as a new fluoroquinolone antibiotic that is a potent and selective inhibitor of the essential bacterial type II topoisomerases and topoisomerase IV. Zabofloxacin is indicated for community-acquired respiratory infections due to Gram-positive bacteria. The aim of this study was to compare the pharmacokinetics (PK) of the zabofloxacin hydrochloride 400 mg capsule (DW224a, 366.7 mg as zabofloxacin) with the PK of the zabofloxacin aspartate 488 mg tablet (DW224aa, 366.5 mg as zabofloxacin) in healthy Korean male volunteers to assess the bioequivalence between the two drug formulations. Methods:A randomized, open-label, single-dose, two-way crossover study was performed. The subjects received either DW224a or DW224aa according to their sequence group. Plasma concentrations of zabofloxacin were determined by liquid chromatography-tandem mass spectrometry. The maximum plasma concentrations (C max ), the area under the plasma concentration versus time curve (AUC) from the time of dosing to 48 hours post-dosing (AUC last ), and the AUC extrapolated to infinity (AUC inf ) were determined from the plasma concentration-time profile. (ClinicalTrials.gov identifier: NCT01341249). Results:Twenty-nine of the 32 subjects enrolled completed the study. The C max , AUC last , and AUC inf (mean AE SD) values of DW224a were 1889.7 AE 493.4 ng/mL, 11,110 AE 2005.0 ng*h/mL, and 11,287 AE 2012.6 ng*h/ mL, respectively, and those of DW224aa were 2005.0 AE 341.3 ng/mL, 11,719 AE 2507.5 ng*h/mL, and 11,913 AE 2544.8 ng*h/mL, respectively. The geometric mean ratios (90% confidence intervals) of the C max , AUC last , and AUC inf were 1.08 (1.00-1.17), 1.05 (1.00-1.10), and 1.05 (1.00-1.10), respectively, and were within the bioequivalence acceptance range of 0.8-1.25. Both drugs were well tolerated with no serious adverse events. Conclusion:A single oral dose of DW224a or DW224aa to healthy volunteers appeared to be well tolerated. Both DW224a and DW224aa exhibited comparable PK profiles and were bioequivalent in terms of PK parameters. Further studies in patients are needed to corroborate the result of this study. ! 2013 Informa UK Ltd www.cmrojournal.com Pharmacokinetic comparison of new quinolone zabofloxacins Han et al. 1349

PurposeSYP-1018 is a lyophilized polymeric nanoparticle formulation of voriconazole that is under development for intravenous dosing. This study compared the pharmacokinetic and tolerability profiles of SYP-1018 with those of Vfend®, the marketed formulation of voriconazole. The effect of CYP2C19 polymorphism on the voriconazole pharmacokinetics was also evaluated.MethodsAn open-label, two-treatment, two-period, two-sequence crossover study was conducted in 52 healthy male volunteers, who randomly received a single intravenous infusion of either of the two voriconazole formulations at 200 mg. Blood samples were collected up to 24 hours after drug administration for pharmacokinetic analysis. The plasma concentrations of voriconazole were determined using liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were estimated using a noncompartmental method. CYP2C19 genotype was identified in 51 subjects.ResultsThe geometric mean ratio (90% confidence interval) of SYP-1018 to Vfend® was 0.99 (0.93–1.04) for the maximum plasma concentrations (Cmax) and 0.97 (0.92–1.01) for the area under the concentration–time curve (AUC) from dosing to the last quantifiable concentration (AUClast). Nineteen homozygous extensive metabolizers (EMs, *1/*1), 19 intermediate metabolizers (IMs, *1/*2 or *1/*3), and ten poor metabolizers (PMs, *2/*2, *2/*3, or *3/*3) were identified, and the pharmacokinetic comparability between SYP-1018 and Vfend® was also noted when analyzed separately by genotype. The systemic exposure to voriconazole was greatest in the PM group, followed by the IM, and then the EM groups. Furthermore, the intrasubject variability for Cmax and AUClast was greater in IMs and PMs than in EMs. No serious adverse event occurred, and both treatments were well tolerated.ConclusionSYP-1018 had comparable pharmacokinetic and tolerability profiles to Vfend® after a single intravenous infusion. CYP2C19 genotype affected not only the pharmacokinetics of voriconazole, but its intrasubject variability. SYP-1018 can be further developed as a clinically effective alternative to Vfend®.

BackgroundHCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium).Subjects and methodsAn open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO®) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration–time curve from 0 to the last measurable time (AUC0−t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study.ResultsSixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0−t (mean ± standard deviation) for naproxen in HCP1004 were 61.67±15.16 µg/mL and 1,206.52±166.46 h·µg/mL, respectively; in VIMOVO®; these values were 61.85±14.54 µg/mL and 1,211.44±170.01 h·µg/mL, respectively. The Cmax and AUC0−t for esomeprazole in HCP1004 were 658.21±510.91 ng/mL and 1,109.11±1,111.59 h·ng/mL, respectively; for VIMOVO®, these values were 595.09±364.23 ng/mL and 1,015.12±952.98 h·ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO®) of the Cmax and AUC0−t of naproxen were 0.99 (0.94–1.06) and 1.00 (0.98–1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0−t were 0.99 (0.82–1.18) and 1.04 (0.91–1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment.ConclusionThe PK of HCP1004 500/20 mg was comparable to that of VIMOVO® 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

BackgroundSeveral 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.MethodsGentamicin 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.ResultsGentamicin 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.ConclusionGentamicin 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.