@article{f819c25ce0834fd39ad01f91179e894e,
title = "Population pharmacokinetics and safety of solithromycin following intravenous and oral administration in infants, children, and adolescents",
abstract = "Solithromycin is a novel fluoroketolide antibiotic which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age, 6 years [age range, 4 days to 17 years]) were administered intravenous (i.v.) or oral (capsules or suspension) solithromycin (i.v., 6 to 8 mg/kg of body weight; capsules/suspension, 14 to 16 mg/kg on days 1 and 7 to 15 mg/kg on days 2 to 5). PK samples were collected after the first and multidose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (n 13; median age, 16 years [age range, 12 to 17 years]) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and postmenstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg i.v. daily and oral dosing of 20 mg/kg on day 1 (800-mg adult maximum) followed by 10 mg/kg on days 2 to 5 (400-mg adult maximum) would achieve a pediatric solithromycin exposure consistent with the exposures observed in adults. Seventy-six treatment-emergent adverse events (TEAEs) were reported in 40 subjects. Diarrhea (6 subjects) and infusion site pain or phlebitis (3 subjects) were the most frequently reported adverse events related to treatment. Two subjects experienced TEAEs of increased hepatic enzymes that were deemed not to be related to the study treatment. (The phase 1 pediatric studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01966055 and NCT02268279.)",
keywords = "Antibiotics, Pediatrics, Pharmacokinetics, Safety, Solithromycin",
author = "{SOLI-PEDS Program} and Daniel Gonzalez and James, {Laura P.} and Amira Al-Uzri and Miroslava Bosheva and Adler-Shohet, {Felice C.} and Mendley, {Susan R.} and Bradley, {John S.} and Claudia Espinosa and Eva Tsonkova and Kathryn Moffett and Lucila Marquez and Simonsen, {Kari A.} and Stefan Stoilov and Felix Boakye-Agyeman and Theresa Jasion and Hornik, {Christoph P.} and Robert Hernandez and Benjamin, {Daniel K.} and Michael Cohen-Wolkowiez",
note = "Funding Information: This research was sponsored by the U.S. Biomedical Advanced Research and Development Authority (HHSO100201300009C), which has a contract with Melinta Therapeutics, Inc., to perform the study. Daniel Gonzalez receives support for research from the National Institute of Child Health and Human Development (K23HD083465). Participants from the Biomedical Advanced Research and Development Authority included James King, Claiborne Hughes, and Shar{\textquoteright}Ron DeDreu. Participants from Melinta Therapeutics, Inc., Chapel Hill, NC, USA, included Brian Jamieson, Robert Hernandez, David Oldach, and Melissa Allaband. Participants from the Duke Clinical Research Institute, Durham, NC, USA, included Adam Silverstein (statistician), Felix Boakye-Agyeman (pharmacokineticist), Danielle Sutton (data management), Elizabeth VanDyne (safety), Carrie Elliott (lead clinical research associate), Theresa Jasion (project leader), and Christoph Hornik. The following participants were from the indicated clinical trial sites: Laura P. James (principal investigator [PI]) and Carol Pierce (study coordinator [SC]), Arkansas Children{\textquoteright}s Hospital Research Institute, Little Rock, AR, USA; Ram Yogev (PI) and Laura Fearn (SC), Lurie Children{\textquoteright}s Hospital of Chicago, IL, USA; Amira Al-Uzri (PI) and Kira Clark (SC), Oregon Health and Science University, Portland, OR, USA; Miroslava Boshevae (PI), Medical University, Plovdiv, Bulgaria; Felice C. Adler-Shohet (PI) and Stephanie Osborne (SC), CHOC Children{\textquoteright}s, Orange, CA, USA; Susan R. Mendley (PI) and Donna Cannonier (SC), University of Maryland School of Medicine, Baltimore, MD, USA; Munib Daudjee (PI) and Jessica Orsak (SC), Mercury Clinical Research, Houston, TX, USA; John S. Bradley (PI) and Sara Hingtgen (SC), Rady Children{\textquoteright}s Hospital—San Diego and the University of California San Diego, San Diego, CA, USA; Claudia Espinosa (PI) and Andrew Michael (SC), Kosair Children{\textquoteright}s Hospital, Louisville, KY, USA; Eva Tsonkovak (PI), Multiprofile Hospital for Active Treatment, Ruse, Bulgaria; Kathryn Moffett (PI) and Tammy Carrington (SC), West Virginia University Hospital, Morgantown, WV, USA; Lucila Marquez (PI) and Farida Lalani (SC), Baylor College of Medicine and Texas Children{\textquoteright}s Hospital, Houston, TX, USA; Kari A. Simonsen (PI) and Kym Abraham (SC), University of Nebraska Medical Center, Omaha, NE, USA; Stefan Stoilov (PI), University Multiprofile Hospital for Active Treatment and Emergency Medicine “N. I. Pirogov,” Sofia, Bulgaria; Barry Bloom (PI) and Paula Delmore (SC), Wesley Medical Center, Wichita, KS, USA; John Vanchiere (PI) and Lisa Latiolais (SC), Louisiana State University Medical Center, New Orleans, LA, USA; Joshua Wolf (PI) and Kim Allison (SC), St. Jude Children{\textquoteright}s Research Hospital, Memphis, TN, USA; Nathan Price (PI) and Gretchen Cress (SC), University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Rachel Orscheln (PI) and Susan Jones (SC), Saint Louis Children{\textquoteright}s Hospital, St. Louis, MO, USA; and Water Dehority (PI) and Christina Batson (SC), University of New Mexico, Department of Pediatrics, Albuquerque, NM, USA. D. Gonzalez and M. Cohen-Wolkowiez wrote the manuscript; F. Boakye-Agyeman, D. Gonzalez, and M. Cohen-Wolkowiez analyzed the data; D. Gonzalez and M. Cohen-Wolkowiez designed the research; D. Gonzalez, L. P. James, A. Al-Uzri, M. Bosheva, F. C. Adler-Shohet, S. R. Mendley, J. S. Bradley, C. Espinosa, E. Tsonkova, K. Moffett, L. Marquez, K. A. Simonsen, S. Stoilov, F. Boakye-Agyeman, T. Jasion, C. P. Hornik, R. Hernandez, D. K. Benjamin, Jr., and M. Cohen-Wolkowiez performed the research. Funding Information: This research was sponsored by the U.S. Biomedical Advanced Research and Development Authority (HHSO100201300009C), which has a contract with Melinta Therapeutics, Inc., to perform the study. Daniel Gonzalez receives support for research from the National Institute of Child Health and Human Development (K23HD083465). Publisher Copyright: Copyright {\textcopyright} 2018 American Society for Microbiology. All Rights Reserved.",
year = "2018",
month = aug,
doi = "10.1128/AAC.00692-18",
language = "English (US)",
volume = "62",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "8",
}