Introduction: Cystic fibrosis (CF) is a genetic condition characterised by severe lung disease often requiring frequent hospital admissions for pulmonary exacerbations requiring intravenous antibiotic treatment. Tobramycin, an aminoglycoside antibiotic, is commonly used to treat pulmonary exacerbations in those with Pseudomonas aeruginosa infections; however, it is unknown whether current paediatric dosing regimens achieve safe and effective plasma concentrations.
Aims: To develop a population pharmacokinetic model (popPK) of tobramycin in children with CF and determine the attainment of a steady state serum AUC24 of 80-110 mg.h/L with standard dosing with the view to creating an optimised dosing strategy to achieve the target AUC24.
Methods: Multicentre prospective audit in children aged ≤19 years with CF over a 13-month period receiving 10mg/kg intravenous tobramycin administered once-daily [1, 2]. Plasma tobramycin concentrations were measured as per routine care based on The Royal Children’s Hospital or Children’s Hospital Westmead guidelines depending on study site. The PopPK model was developed using the FOCEI method in NONMEM 7.5.1. The AUC24 was calculated for each patient (based on their dose and individual parameter estimates) and compared to the accepted target range.
Results: Overall, 450 plasma tobramycin concentrations from 64 CF patients who received 96 courses were included. The median age was 13.6 years (range 0.2-19.3), median weight 44.5 kg (range 5-81.7) and median serum creatinine 43 mcM (range 14-107). The final popPK model was a one-compartment model with linear elimination and included a maturation function with fixed coefficients as per Anderson & Holford (2009) [3], weight and estimated glomerular filtration rate (eGFR) (modified Schwartz equation) on clearance (CL) and weight on volume (V). The exponent for the influence of eGFR on CL was 0.4 (fixed) and for weight on CL and V were estimated to be 0.646 and 0.711, respectively. Concomitant use of cystic fibrosis transmembrane receptor modulators did not influence CL or V. The estimated population CL was 6.23 L/h/70kg and V was 15.4 L/70kg. With standard dosing, 32/64 (50%) patients achieved an AUC24 within target ranges of 80-110 mg/L·h in their first course, and across all courses the target AUC24 was achieved in 52/96 (54%)
Discussion: Standard tobramycin dosing achieves the target AUC24 in only 54% of children. An optimised dosing strategy is needed to better achieve the target AUC24.
References:
- Royal Children’s Hospital (2023). Medication Guideline: Tobramycin in Cystic Fibrosis.
- The Children’s Hospital at Westmead (2021). Aminoglycoside dosing and monitoring – CHW practice guideline.
- Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug metabolism and pharmacokinetics. 2009;24(1):25-36.