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

Alghanem, S. S., Touw, D. J. & Thomson, A. H., Aug-2019, In : Journal of Antimicrobial Chemotherapy. 74, 8, p. 2311-2317 7 p.

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

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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.

Original languageEnglish
Pages (from-to)2311-2317
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number8
Publication statusPublished - Aug-2019

ID: 91992679