Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

Abstract

Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC ratio of >125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one-and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained Acute pulmonary exacerbations requiring antibiotic and airway clearance therapy are the most frequent complication of cystic fibrosis (CF). Acute exacerbations occur as a result of a flare-up of the chronic infection within the lower airways. In this scenario, the therapeutic goals include reduction of bacterial density and improvement of pulmonary function and nutritional status (16). Therefore, the primary therapeutic approach is institution of antimicrobial therapy directed against the most commonly encountered pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae.Ciprofloxacin is a second-generation fluoroquinolone with a broad spectrum of activity. It possesses potent bactericidal activity against P. aeruginosa isolates from CF patients (1, 18). In addition, ciprofloxacin has consistently demonstrated synergistic activity with other antipseudomonal agents against multiple-drug-resistant P. aeruginosa isolates obtained from CF patients (18). With these attributes, it is not surprising that ciprofloxacin is frequently prescribed for the treatment of pulmonary exacerbations in CF patients.The pharmacokinetics of ciprofloxacin have been extensively evaluated in stable CF patients (4,9,11,14,17,20,23). Results of these studies indicate no significant alterations in pharmacokinetics when patients are compared with normal healthy volunteers. In contrast, data on the pharmacokinetics of ciprofloxacin during acute pulmonary exacerbations are limited (2, 21). In addition, none of these studies performed compartmental pharmacokinetic analysis, which would permit dosage individualization for the patient. Studies performed in non-CF patients with nosocomially acquired lower respiratory tract infections demonstrated that optimal clinical and bacteriological outcomes are associated with achievement of specific threshold values of pharmacodynamic variables, such as the area under the concentration time curve from 0 to 24 h (AUC 0-24 )/MIC ratio and peak/MIC ratio (6, 15). Specifically, Forrest et al. demonstrated that optimal clinical and bacteriological responses in non-CF patients with lower respiratory tract infections are associated with the abili...

Pharmacokinetic Parameters of Ciprofloxacin in Bangladeshi Volunteers: A Preliminary Evaluation

“…16 The AUC 0-12h obtained in the present study for oral route in case of Tribal was comparable to the findings of previous study, 13 although the values for Bangalee were low.…”

“…23 The C max observed in the present study after oral administration was modestly higher in case of Tribal and lower in case of Bangalee Bangladeshi in relation to the findings of the previous studies probably due to the dissimilarity in the population studied. Regarding intravenous route, one study 16 has provided idea about the AUC 0-12h and C max. , which are in cystic fibrosis patients and were 48.3 μg h/mL and 2.9 μg/mL respectively.…”

“…14 There are different methods to estimate ciprofloxacin in plasma, especially by HPLC 9,[15][16] , however, the initial challenge was to establish a suitable method to estimate plasma ciprofloxacin in laboratories of Bangladesh. Therefore, the aim of this study was to establish a method of estimation of ciprofloxacin in plasma as well as to get preliminary idea about the pharmacokinetic behaviour of Bangladeshi healthy volunteers of two different ethnic groups.…”

Need for Susceptibility Testing Guidelines for Fastidious or Less-Frequently Isolated Bacteria

“…The recognition of the importance of the time the drug levels in blood are maintained above the drug's proposed MIC breakpoint (T Ͼ MIC; with beta-lactams, glycopeptides, macrolides) or the area under the drug concentration curve in blood divided by the proposed MIC breakpoint (with aminoglycosides or fluoroquinolones) have contributed to the ability to set appropriate breakpoints (5). Simulations such as the Monte Carlo analysis (22) have allowed an assessment of the likelihood of achieving sufficient drug levels at the site of the most common infections by using various dosing regimens of a drug. Lastly, the AST subcommittee reviews clinical and bacteriological response data collected during large clinical trials of a new agent when they establish breakpoints.…”

Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141

“…Monte Carlo simulation (MCS) of antimicrobial dosing regimens is a powerful tool for determining the probability of achieving a specific PDI value defined as a target attainment rate (TAR) (9,10). MCS has been used for AUC-dependent drugs (1,8,15,19,25), whereby TARs are obtained for selected values of AUC/MIC ratios. An appropriate dosing regimen can be chosen or a breakpoint value (given the dosing regimen) projected from TARs obtained for various simulated dosing regimens, taking into consideration the population distributions of the MICs of a given target pathogen.…”