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PAGE 2021: Clinical Applications
Zoe Kane

Development of a neonatal plasma and cerebrospinal fluid (CSF) population PK model for fosfomycin.

Zoe Kane (1), Silke Gastine (1), Phoebe Williams (3,4), Sally Ellis (5), James A Berkley (3,4), Christina Obiero (3), Mike Sharland (2), Joseph Standing (1)

(1) Great Ormond Street Institute of Child Health, University College London, London, UK (2) Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St. George’s, University of London, London, UK (3) KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya (4) Centre for Tropical Medicine & Global Health, University of Oxford, UK (5) Global Antibiotic Research and Development Partnership, Geneva, Switzerland

Objectives: Fosfomycin is a potential component of empiric antimicrobial treatment where resistance to ampicillin or cefotaxime/gentamicin (SOC) is high1. Fosfomycin PK data in neonates is very limited. No previous study has collected oral PK, and flip-flop kinetics have been described for some oral products in adults. Here we report the population PK analysis of the NeoFosfo trial.

Methods: NeoFosfo (ClinicalTrials.gov: NCT03453177) enrolled 61 neonates in the arm randomised to receive SOC plus 100mg/kg q12h fosfomycin. Sample size was determined by simulation-estimation. After a minimum of 48 hours patients were stepped down to oral therapy. Two PK samples were taken following the first IV and first oral doses, with timings randomised to cover the whole dose interval in the population. This cross-over design gave >80% power for CL, V and F% estimation. Cerebrospinal fluid (CSF) sampling was opportunistic. PK modelling was performed using the NONMEM 7.3 FOCEI algorithm. A priori allometric weight and postmenstrual age (PMA) scaling was applied, and the following covariates tested: postnatal age (PNA) on CL as a fraction at birth and rate of maturation, serum creatinine on CL scaled by age adjusted expected creatinine, and protein on CSF uptake fraction.

Simulations (n=10,000) of plasma concentrations were performed in the context of two PD targets; AUC:MIC ratio and fT>MIC. Arbitrary targets for fT>MIC were defined (60, 80 and 100%) but for AUC:MIC ratio previously published in-vitro targets for Escherichia coli were employed; stasis (19.3), 1-log kill (87.5)2 and resistance suppression (3136)3.The simulation population was defined using neonatal covariate data from the much larger NeoAMR study (Clinical Trials.gov: NCT03721302). PTA was evaluated for multiple dose levels, following oral or IV dosing.  

Results: Of 238 plasma and 15 CSF concentrations, IV and PO plasma levels ranged (mean) from 7-576 (202) and 7-206 (70) respectively, with CSF from 16-66 (38) µg/mL. A 3-compartment model with first order absorption and fixed allometric and PMA scaling adequately described our data. Further significant covariates were PNA on on CL and CSF protein on uptake into CSF. Adult adjusted population estimates (%RSE/95% CI) for CL and Vc were 8.9 L/hr (14.5% / 7.1-13.2 L/hr) and 19.1 L (8.8% / 11.2-21.3 L), and are in good agreement with PK observed in healthy adults4. Inter-individual variability was 25% (31%) and 14% (42%) respectively. F% was estimated at 48% (15.0%), Ka at 0.1 hr (21.7%) and the BETA phase half life calculated as 2.3 hr. Considering the PNA function, the population estimate of the fraction of clearance on the first day of life is 0.45 and the rate of short-term maturation post birth is 0.12 /day. Parameter estimate precision was 22.9 and 29.4% respectively and the 95% confidence intervals calculated from the bootstrap analysis were 0.28 to 0.57 and 0.05 to 0.26 /day. The volume of the CSF compartment and clearance from the central to CSF compartment were fixed based on scaled adult priors. The CSF protein coefficient was estimated to be -0.95 (-2.88 to -0.62) with a precision of 22.4% while the fraction of fosfomycin penetrating the CSF was 0.32 (0.27 to 0.41) with a precision of 12.0%. For an MIC of 32 µg/mL the probability of a 1-log reduction in bacterial load following a 100mg/kg BD IV regimen is predicted to be only 12% in older term neonates (GA > 36 weeks and PNA >7 days) while this increases to 99% in younger pre-term babies (GA < 32 weeks and PNA ≥ 7 days). Simulations enabled development of an algorithm where by an oral step down dose can be defined at 48hrs once the likely organism and MIC is know, e.g. if MIC <= 8 mg/L, dose (mg/kg) = 200.

Conclusions: To our knowledge this is the first study to report model-based oral bioavailability from cross-over data in a neonatal antimicrobial study, and the first report of neonatal fosfomycin CSF penetration. PNA in addition to PMA was needed to describe immediate post-birth changes in CL distinct from gestational effects. CSF protein is generally known to correlate with CNS penetration and here we also establish a positive relationship between CSF protein and CSF uptake of fosfomycin. Using currently available AUC:MIC targets2,3 the model can be used to select a neonatal IV dose based on a babies GA, PNA and WT and the oral step down dose personalised using likely pathogen MIC at 48 hrs.

[1] Williams, P. C. M. et al. The potential of fosfomycin for multi-drug resistant sepsis: an analysis of in vitro activity against invasive paediatric Gram-negative bacteria. J. Med. Microbiol. 68, 711–719 (2019).
[2] Lepak, A. J. et al. In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 61, (2017).
[3] Docobo-Perez, F. et al. Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance. Antimicrob. Agents Chemother. 59, 5602–5610 (2015).
[4] Wenzler, E., Ellis-Grosse, E. J. & Rodvold, K. A. Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers. Antimicrob. Agents Chemother. 61, (2017).

Reference: PAGE 29 (2021) Abstr 9746 [www.page-meeting.org/?abstract=9746]
Oral: Clinical Applications