IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis

Author:

Kane Zoe12ORCID,Gastine Silke1,Obiero Christina3,Williams Phoebe34,Murunga Sheila3,Thitiri Johnstone3,Ellis Sally5,Correia Erika5,Nyaoke Borna6,Kipper Karin7,van den Anker John89,Sharland Mike10,Berkley James A3411,Standing Joseph F112ORCID

Affiliation:

1. Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK

2. Quotient Sciences, Mere Way, Ruddington, Nottingham, UK

3. KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya

4. Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

5. GARDP—Global Antibiotic Research & Development Partnership, Genève, Switzerland

6. DNDi—Drugs for Neglected Diseases initiative, Nairobi, Kenya

7. Institute of Chemistry, University of Tartu, Tartu, Estonia

8. Department of Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, Switzerland

9. Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA

10. Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George’s, University of London, London, UK

11. The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya

12. Pharmacy Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Abstract

Abstract Background Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking. Objectives To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data. Methods The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed. Results In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347–0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272–0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio. Conclusions Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant’s PMA, PNA and weight.

Funder

German Federal Ministry of Education and Research

German Ministry of Health

South African Medical Research Council

Department for International Development

Ministry of Health, Welfare and Sport of the Netherlands and Médecins Sans Frontiéres

National Institute for Health Research Biomedical Research Centre

Great Ormond Street Hospital for Children NHS Foundation Trust

University College London

United Kingdom Medical Research Council

European Union’s Seventh Framework Programme

REA

Estonian Research Council

Analytical Services International

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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