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Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands

Mase, Sundari R. MD, MPH; Jereb, John A. MD; Gonzalez, Daniel PharmD, PhD; Martin, Fatma MBBS; Daley, Charles L. MD; Fred, Dorina MBBS; Loeffler, Ann M. MD; Menon, Lakshmy R. MPH; Bamrah Morris, Sapna MD; Brostrom, Richard MD; Chorba, Terence MD; Peloquin, Charles A. PharmD, FCCP

The Pediatric Infectious Disease Journal: April 2016 - Volume 35 - Issue 4 - p 414–421
doi: 10.1097/INF.0000000000001022
Antimicrobial Reports
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Background: In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15–20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies.

Methods: Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0–24 hours × μg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8–12 µg/mL.

Results: Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15–20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0–24/MIC) values.

Conclusions: Levofloxacin dosage should be 15–20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0–24/MIC values in children ≥2 years of age.

Supplemental Digital Content is available in the text.

From the *Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; §Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; North Bay Pediatrics, Vallejo, California; Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, Colorado; **TB/Leprosy Program, Federated States of Micronesia (FSM); ††Francis J. Curry International TB Center, San Francisco, California; and ‡‡Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida.

Accepted for publication July 20, 2015.

Supported by Centers for Disease Control and Prevention and National Institute of General Medical Sciences; D.G. is funded by training grant T32GM086330 from the National Institute of General Medical Sciences.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence Sundari R. Mase, MD, MPH, Centers for Disease Control and Prevention, Atlanta, GA 30030. E-mail: fyy0@cdc.gov.

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