Pharmacokinetic-Pharmacodynamic Target Attainment Analyses to Determine Optimal Dosing 1 of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Cystic 2 Fibrosis

24 Background: Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are 25 associated with increased morbidity and mortality in CF. Drug resistance is a significant 26 challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity 27 against isolates recovered from CF; including drug-resistant strains. Altered pharmacokinetics 28 (PK) of several beta-lactam antibiotics have been reported in CF. Therefore, this study sought to 29 characterize the PK of CZA and perform target-attainment analyses to determine the optimal 30 treatment regimen. 31 32 Methods: The PK of CZA was determined from 12 adult CF patients administered 3 33 intravenous doses of 2.5g q8h infused over 2h. Population modeling utilized the maximum34 likelihood expectation method. Monte Carlo simulations determined the probability of target 35 attainment (PTA). Exposure targets of free-ceftazidime (CAZ) above MIC (fT>MIC), and free36 avibactam (AVI) above a 1 mg/L threshold concentration (fT>Ct) were evaluated. Published 37 CAZ and CZA MIC distributions were incorporated to evaluate cumulative response 38 probabilities. 39 40 Results: CAZ and AVI were best described by 1-compartment models. Total body clearances 41 (CAZ CLt: 7.53  1.28 L/h, AVI CLt: 12.30  1.96 L/h) and volumes of distribution (CAZ Vd: 18.80 42 ± 6.54 L, AVI Vd: 25.30 ± 4.43 L) were broadly similar to published healthy adults. CAZ achieved 43 a PTA (50% fT>MIC) > 0.9 for MICs  16 mg/L and AVI PTA (50% fT>Ct of 1.0) >0.99. The 44 overall likelihood of treatment response was 0.82 with CZA vs. 0.42 for CAZ. 45 46 Conclusions: These data demonstrate improved pharmacodynamics of CZA in comparison 47 with CAZ and provide guidance on optimal dosing of (CZA) for future studies. 48 on A uust 0, 2017 by R IC E U N IV E R S IT Y httpaac.asm . rg/ D ow nladed fom INTRODUCTION 49 Cystic fibrosis (CF) is characterized by a chronic cycle of airway obstruction, infection, and 50 inflammation resulting to progressive loss of lung function, culminating in respiratory failure and 51 death (1). Disease progression occurs through intermittent episodes of acute pulmonary 52 exacerbations (APE), whereby overall lung function does not completely return to previous 53 baseline values. (2, 3). The frequency of APE is associated with negative health outcomes 54 including death (2, 4-6). 55 56 Administration of systemic antibiotics and airway clearance therapies are the primary therapies 57 for treatment of APE. Two randomized studies have demonstrated intravenous antibiotic 58 treatment for APE is associated with improvement in pulmonary function (7, 8). P. aeruginosa is 59 the principal pathogen in the CF population with a prevalence of 70% in adults (9). 60 61 A significant challenge to treatment is the occurence of MDR strains of P. aeruginosa which is 62 present in the airways of nearly one-third of patients (9). Antipseudomonal beta-lactams 63 including ceftazidime (CAZ) are frequently prescribed for treatment of APE; however, the 64 increasing prevalence of resistance is cause for concern (9, 10). Ceftazidime-avibactam (CZA), 65 a β-lactam/non-β-lactam β-lactamase inhibitor combination, offers a significant advancement in 66 the management of P. aeruginosa in CF due to improved activity against CAZ resistant isolates 67 (10, 11). 68 69 The pharmacokinetics of a number of antibiotics including beta-lactams have been shown to be 70 altered in patients with CF. (12, 13). The purpose of this study is to characterize the steady71 state pharmacokinetics of CZA and perform pharmacodynamic target attainment analyses to 72 determine the optimal dosing regimen in preparation for future studies evaluating the efficacy 73 and safety in treatment of APE in patients with CF. 74 on A uust 0, 2017 by R IC E U N IV E R S IT Y httpaac.asm . rg/ D ow nladed fom