Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis During Acute Pulmonary Exacerbation.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY(2020)
摘要
Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (V-c) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (V-theta) normalized by the median observed value (V-c = V-theta x TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CL theta + CRCL), where CLNR represents nonrenal clearance and CL theta represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: V-theta, 4.92 +/- 0.76 liters.kg(-1); CLNR, 0.59 +/- 0.30 liters.h(-1); CL theta, 5.97 x 10(-3) +/- 1.24 x 10(-3); V-p (volume of the peripheral compartment), 3.77 +/- 1.41 liters; Q (intercompartmental clearance), 4.08 +/- 2.17 liters.h(-1). The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 +/- 4.6 and 52 +/- 12 mg.h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of <= 0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg.h.liter(-1)) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults.
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关键词
Monte Carlo simulation,acute pulmonary exacerbation,cystic fibrosis,dose,glycopeptides,pharmacokinetics,probability of target attainment,telavancin
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