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

Alghanem, S. S. and Touw, D. J. and Thomson, A. H. (2019) Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453

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    Abstract

    Objectives: To determine the outcomes of weight (WT) and height (HT) based tobramycin dosing regimens for patients with cystic fibrosis (CF). Methods: A simulated data set of 5000 patients based on 331 patients with CF was created using NONMEM. 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/PD indices were a Cmax/MIC ratio ≥10 and AUC0-24/MIC ≥110. For these indices and a range of MICs, cumulative fractions of response (CFR) 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%). AUC0-24 estimates >120 mg.h/L were more common with WT-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 of the target micro-organism 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. HT-based doses should therefore be considered for patients with CF.