Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis

Abstract

Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate at 200 mg orally or intravenously once daily for 3 doses with a minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetic analysis was performed using the maximum likelihood expectation maximization method, and the disposition of TZD was described by a two-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean sputum-to-unbound plasma penetration ratio of 2.88 (coefficient of variation, 50.3%). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 liters/h, 61.6 ± 6.94 liters, and 1.04 ± 0.232, respectively. The total clearance was higher in CF patients than in healthy volunteers; however, it was similar to published data for patients with complicated skin and skin structure infections (cSSSIs). This study demonstrates that the oral bioavailability of tedizolid is excellent in patients with CF and that the plasma pharmacokinetics are similar to those reported for patients with cSSSIs.

Keywords: cystic fibrosis; pharmacokinetics; tedizolid.

FIG 1

Concentration-time profiles (mean ± SD) following the third dose of tedizolid at 200 mg in plasma (A), plasma over the first 8 h (B), sputum and unbound plasma (C), and sputum and unbound plasma over the first 8 h (D) in patients with cystic fibrosis.

FIG 2

Goodness-of-fit plots of the final PK model. Observed TZD concentrations versus individual model-predicted concentrations in plasma (R² = 0.91; slope ± SE = 1.034 ± 0.02279) (A) and sputum (R² = 0.93; slope ± SE = 0.9599 ± 0.04912) (B), conditional standardized residuals versus model prediction in plasma (C) and sputum (D), and observed TZD concentrations versus population model-predicted concentrations in plasma (R² = 0.77; slope ± SE = 0.994 ± 0.03849) (E) and sputum (R² = 0.54; slope ± SE = 0.6954 ± 0.1166) (F) using linear regression are shown.

FIG 3

Structural model of the plasma and sputum pharmacokinetics of TZD following i.v. and oral administration in each subject. CL_t, total clearance; CL_d, distributional clearance; V_c, central volume of distribution; V_p, peripheral volume of distribution; K_a, absorption rate constant; F, bioavailability; r(t), intravenous infusion; b, bolus dose.