Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis

Abstract

Abstract Objectives To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF). Methods A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20–30 and 20–40 mg/L) and AUC0–24 (80–120 and 80–150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0–24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined. Results More patients achieved standard Cmax and AUC0–24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0–24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0–24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0–24 targets. Conclusions A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0–24 ranges were narrower and the incidence of high AUC0–24 values was lower. Height-based doses should therefore be considered for patients with CF.