Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

ABSTRACT

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_θ) normalized by the median observed value (V_c = V_θ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CL_NR + CL_θ × CRCL), where CL_NR represents nonrenal clearance and CL_θ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: V_θ, 4.92  ± 0.76 liters · kg⁻¹; CL_NR, 0.59  ± 0.30 liters · h⁻¹; CL_θ, 5.97 × 10⁻³ ± 1.24 × 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. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)