Abstract
Purpose: The aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies. Methods: A population PK model was developed using opportunistically collected plasma samples. For each dosing strategy, model-based probability of target attainment (PTA) estimates were computed for study participants using empirical Bayes estimates. In addition, the effects of body size and renal function on PTA were evaluated using stochastic model simulations with virtually generated subjects. Results: Twenty-nine participants, 24 of whom were obese, contributed data towards the analysis. The median (range) age, body weight, and body mass index of participants were 12.2 years (2.3–20.6), 59.2 kg (8.4–121), and 25.2 kg/m2 (13.8–42.9), respectively. Administration of 50 mg/kg intravenously (IV) every 8 hours (q8h; max 6 g/day) or 40 mg/kg IV q6h (max 6 g/day) resulted in PTA values of ≥ 90% (minimum inhibitory concentration 8 mg/L) for the subset of obese participants with estimated glomerular filtration rates (GFR) ≥ ~ 80 mL/min/1.73 m2. However, for both regimens, stochastic model simulations denoted lower PTA values (< 90%) with increasing body weight for virtual subjects with GFR ≥ 120 mL/min/1.73 m2. Alternatively, permitting for a maximum daily dose of 8 g/day using a 40 mg/kg IV q6h regimen provided PTA values that were near or above target (90%) for virtual subjects between 10 to 120 kg with GFR ≥ 80 mL/min/1.73 m2. Conclusion: Our analysis suggests administration of 40 mg/kg IV q6h (max 8 g/day) maximizes PTA in children and adolescents with obesity and GFR ≥ 80 mL/min/1.73 m2. Trial Registration: Clinicaltrials.gov Identifier: NCT01431326.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 499-513 |
| Number of pages | 15 |
| Journal | Pediatric Drugs |
| Volume | 23 |
| Issue number | 5 |
| DOIs | |
| State | Published - Sep 2021 |
Funding
ARM receives support from the Thrasher Research Fund’s Early Career Award. CPH receives salary support for research from National Institute for Child Health and Human Development (NICHD) (R13HD102136), the National Heart Lung and Blood Institute (NHLBI) (R61/R33HL147833), the US Food and Drug Administration (R01-FD006099, PI Laughon; and U18-FD006298, PI: Benjamin), the US government for his work in pediatric clinical pharmacology (Government Contract HHSN275201800003I, PI: Benjamin under the Best Pharmaceuticals for Children Act), the non-profit Burroughs Wellcome Fund, and other sponsors for drug development in adults and children ( https://dcri.org/about-us/conflict-of-interest/ ). DKB Jr. receives support from the National Institutes of Health National Institute of Child Health and Human Development (HHSN275201000003I), the National Center for Advancing Translational Sciences (1U24TR001608), and Food and Drug Administration (1U18FD006298); he also receives research support from industry for neonatal and pediatric drug development. JA receives salary support from the FRQS (Fonds de Recherche Santé Québec), and does consulting for Astellas Pharma Inc. JES receives salary support for research from the National Institute for Health (NIH) (2UG1OD024954 and 1UG1HD090904-01), Environmental Health Sciences Core Centers (EHSCC), NIH 1P30ES030283-01A1, and her work in pediatric clinical pharmacology (subcontract with Duke University under Government Contract HHSN275201800003I), and other sponsors/industry for drug development in infants and children. KOZ receives salary support from the National Institutes of Health National Institute of Child Health and Human Development (K23 HD091398, HHSN275201000003I), the US Food and Drug Administration (UG3/UH3 FD 006797), the Duke Clinical and Translational Science Award (KL2TR001115-03), and industry for neonatal and pediatric drug development ( http://ww.dcri.duke.edu/research/coi.jsp ). All other authors do not have relevant conflicts of interest. The assay measuring ceftazidime plasma concentrations was developed and performed at OpAns, LLC (Durham, NC, USA). PTN Steering Committee Members: Daniel K. Benjamin Jr., Christoph Hornik, Kanecia Zimmerman, Phyllis Kennel, and Rose Beci, Duke Clinical Research Institute, Durham, NC; Chi Dang Hornik, Duke University Medical Center, Durham, NC; Gregory L. Kearns, Independent Arkansas Children’s Hospital Research Institute, Little Rock, AR; Matthew Laughon, University of North Carolina at Chapel Hill, Chapel Hill, NC; Ian M. Paul, Penn State College of Medicine, Hershey, PA; Janice Sullivan, University of Louisville, Louisville, KY; Kelly Wade, Children's Hospital of Philadelphia, Philadelphia, PA; Paula Delmore, Wichita Medical Research and Education Foundation, Wichita, KS, USA. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): Perdita Taylor-Zapata and June Lee. The Emmes Company, LLC Corporation (Data Coordinating Center): Ravinder Anand, Gaurav Sharma, Gina Simone, Kim Kaneshige, and Lawrence Taylor. PTN Publication Committee: Chaired by Thomas Green, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA. Pediatric Trials Network’s Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care Study Team and Study Coordinators: Duke Clinical Research Institute: Chiara Melloni (PI), Barrie Harper (PL), Adam Samson (L-CRA), Tammy Day (CRA). Hospital Sainte-Justine: Julie Autmizguine (PI), Mariana Dumitrascu (SC). Ann and Robert H. Lurie Children’s Hospital of Chicago: William Muller (PI), Laura Fearn (SC). Oregon Health and Science University: Amira Al-Uzri (PI), Kira Clark (SC). University of Utah Hospitals and Clinics: Catherine Sherwin (PI), Sharada Dixit (SC). Cincinnati Children Hospital Medical Center: Stuart Goldstein (PI), Teresa Mottes (SC), Tara Terrell (SC). Duke University Medical Center: Chi Hornik (PI), Melissa Harward (SC). The Children's Hospital Research Institute of Manitoba, Inc.: Geert T'Jong (PI), Jeanninne Schellenberg (SC). The Hospital for Sick Children: Yaron Finkelstein (PI), Maggie Rumantir (SC). University of Florida Center for HIV/AIDS Research Education and Service (UF CARES): Mobeen H. Rathore, MD (PI), Kathleen Thoma (SC). This work was funded under the National Institute of Child Health and Human Development (NICHD) contract [HHSN275201000003I] for the Pediatric Trials Network (PI Danny Benjamin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- Pharmacology (medical)
- Pediatrics, Perinatology, and Child Health
