(256) Tobramycin Pharmacokinetic Differences in Patients After Initiation of Highly Effective Modulator Therapy

Background: Patients with cystic fibrosis (PwCF) receive numerous courses of antibiotics throughout their lifetime to treat infections, including Pseudomonas aeruginosa. Based on the Cystic Fibrosis Foundation guidelines for treatment of pulmonary exacerbations, P. aeruginosa should be treated with a combination of two antibiotics with different mechanisms of action, one of which is likely to be an intravenous (IV) aminoglycoside dosed using once-daily dosing. PwCF are known to have pharmacokinetic differences from patients without CF, including increased clearance and volume of distribution (V_d) that often necessitate higher and/or more frequent medication dosing to achieve therapeutic concentrations. The mechanisms underlying differences in aminoglycoside clearance are poorly understood, but could related to loss of CFTR function or difference in Vd due to body composition differences. We asked, therefore, whether restored CFTR function via HEMT would impact aminoglycoside pharmacokinetics and require modified dosing.

Methods: This was a retrospective review of all patients receiving extended interval IV tobramycin therapy for treatment of a CF exacerbation with at least one course of tobramycin both before and after initiation of elexacaftor/tezacaftor/ivacaftor. Analysis was limited to those PwCF who were documented to achieve therapeutic concentrations with traditional extended interval goal ranges. For patients receiving multiple courses prior to initiation of HEMT, the mean of the pharmacokinetics of the three most recent courses within two years pre-HEMT was collected. While some patients also received multiple courses post-HEMT, the most recent course (i.e. with the longest interval of the patient on elexacaftor/tezacaftor/ivacaftor) was selected for comparison.

Results: Overall, 17 patients with an average age of 26.7 years (range 13.9-37.6 years) were included in this analysis. In the two years prior to elexacaftor/tezacaftor/ivacaftor, patients received an average of 2.4 courses of IV tobramycin. Post-HEMT, patients received a range of one to seven courses of IV tobramycin (0.37-26.07 months after initiation). Table 1 shows the pre- and post-HEMT IV tobramycin characteristics, including dose per kilogram (dose/kg), V_d per kilogram (V_d/kg) and elimination rate (k_e). No significant differences were noted in renal function before and after initiation of HEMT, measured by blood urea nitrogen (12.2 + 3.9 mg/dL vs 14.2 + 5.3 mg/dL, p=0.25) and serum creatinine (0.67 + 0.13 mg/dL vs 0.76 + 0.18 mg/dL, p=0.15).

Conclusions: In this small patient population, the pharmacokinetic parameters of IV tobramycin (including dose/kg, V_d, and k_e) did not appear to change significantly after initiating chronic therapy with a HEMT. However, larger studies are warranted both now and in the future as patients remain on HEMT long term.

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