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      Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects

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          Abstract

          Background and Objectives

          Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects.

          Methods

          Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo.

          Results

          After a single infusion of dalbavancin, the maximal plasma concentration ( C max) and area under the plasma concentration–time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg ( C max: 157 μg/ml and 299 μg/ml; AUC last: 10,850 μg·h/ml and 22,679 μg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life ( t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group.

          Conclusions

          Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

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          Most cited references16

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          Prediction of Creatinine Clearance from Serum Creatinine

          A formula has been developed to predict creatinine clearance (C cr ) from serum creatinine (S cr ) in adult males: Ccr = (140 – age) (wt kg)/72 × S cr (mg/100ml) (15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18–92. Values for C cr were predicted by this formula and four other methods and the results compared with the means of two 24-hour C cr’s measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr·s of 0.83; on average, the difference between predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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            Once-weekly dalbavancin versus daily conventional therapy for skin infection.

            Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection.
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              Extended-duration dosing and distribution of dalbavancin into bone and articular tissue.

              Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC90 for Staphylococcus aureus of 0.06 μg/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g. A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed.
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                Author and article information

                Contributors
                860-876-0607 , Michael.w.dunne@comcast.net
                Journal
                Clin Drug Investig
                Clin Drug Investig
                Clinical Drug Investigation
                Springer International Publishing (Cham )
                1173-2563
                1179-1918
                12 October 2015
                12 October 2015
                2015
                : 35
                : 12
                : 785-793
                Affiliations
                [ ]Durata Therapeutics, Inc., 322 East Main Street, Branford, CT 06405 USA
                [ ]Parexel International, Early Phase Clinical Unit-Los Angeles, 1560 Chevy Chase Drive, Suite 140, Glendale, CA 91206 USA
                Article
                340
                10.1007/s40261-015-0340-4
                4659844
                26458939
                b547c243-8ab9-45ff-b741-cc170ba73699
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                Original Research Article
                Custom metadata
                © Springer International Publishing Switzerland 2015

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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