Physiologically Based Pharmacokinetic Modeling To Guide Management of Drug Interactions between Elexacaftor-Tezacaftor-Ivacaftor and Antibiotics for the Treatment of Nontuberculous Mycobacteria.

Nontuberculous mycobacteria (NTM) are the pathogens of concern in people with cystic fibrosis (pwCF) due to their association with deterioration of lung function. Treatment requires the use of a multidrug combination regimen, creating the potential for drug-drug interactions (DDIs) with cystic fibrosis transmembrane conductance regulator (CFTR)-modulating therapies, including elexacaftor, tezacaftor, and ivacaftor (ETI), which are eliminated mainly through cytochrome P450 (CYP) 3A-mediated metabolism. An assessment of the DDI risk for ETI coadministered with NTM treatments, including rifabutin, clofazimine, and clarithromycin, is needed to provide appropriate guidance on dosing. The CYP3A-mediated DDIs between ETI and the NTM therapies rifabutin, clarithromycin, and clofazimine were evaluated using physiologically based pharmacokinetic (PBPK) modeling by incorporating demographic and physiological "system" data with drug physicochemical and in vitro parameters. Models were verified and then applied to predict untested scenarios to guide continuation of ETI during antibiotic treatment, using ivacaftor as the most sensitive CYP3A4 substrate. The predicted area under the concentration-time curve (AUC) ratios of ivacaftor when coadministered with rifabutin, clofazimine, or clarithromycin were 0.31, 2.98, and 9.64, respectively, suggesting moderate and strong interactions. The simulation predicted adjusted dosing regimens of ETI administered concomitantly with NTM treatments, which required delayed resumption of the standard dose of ETI once the NTM treatments were completed. The dosing transitions were determined based on the characteristics of the perpetrator drugs, including the mechanism of CYP3A modulation and their elimination half-lives. This study suggests increased doses of elexacaftor/tezacaftor/ivacaftor 200/100/450 mg in the morning and 100/50/375 mg in the evening when ETI is coadministered with rifabutin and reduced doses of elexacaftor/tezacaftor 200/100 mg every 48 h (q48h) and ivacaftor 150 mg daily or a dose of elexacaftor/tezacaftor/ivacaftor 200/100/150 mg q72h when coadministered with clofazimine or clarithromycin, respectively. Importantly, the PBPK simulations provide evidence in support of the use of treatments for NTM in pwCF receiving concomitant dose-adjusted ETI therapy.

Economic aspects of antibacterial adverse effects.

The economic impact of adverse effects is often understated. Increased hospitalisations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Although most classes of antibacterials are well tolerated, severe reactions do occur and can add significantly to the cost of care. Among hospitalised patients, antibacterial adverse effects account for nearly 25% of adverse drug reactions. Published pharmacoeconomic data on direct and indirect costs of antibacterial adverse effects are lacking. The importance of determining the most cost-effective treatment regimen is becoming more apparent due to limited resources available within the healthcare system. When considering the cost of new antibacterials, a simple comparison of acquisition costs may not accurately reflect the true costs of treatment. A drug with a lower acquisition cost may be more toxic and/or less effective, resulting in higher complication rates and/or treatment failures, thus leading to a higher overall treatment cost. In addition, nephrotoxic agents such as aminoglycosides and vancomycin often require close monitoring of serum drug concentrations and creatinine levels, which also contributes to the total cost of therapy. Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials. Institutions must evaluate a drug's potential for causing and adverse event, among various other factors, when considering drugs for inclusion on their formularies. Drugs with good safety profiles may minimise hospitalisation or facilitate early discharge. Thus, the adverse effect profile of an antimicrobial agent can contribute significantly to its overall direct costs, primarily as a result of higher monitoring costs and additional days of hospitalisation. For example, in the US, the cost associated with adverse effects, such as nephrotoxicity, observed with aminoglycosides and vancomycin, may add approximately $US2500 per patient with nephrotoxicity (1990 values). Indirect costs can also be substantial as a result of reduced productivity. Many adverse effects of antibacterial agents are predictable and may be minimised with appropriate monitoring and care. This article reviews the pharmacoeconomic aspects of adverse effects associated with some of the more important antibacterial classes such as the beta-lactams, aminoglycosides, vancomycin, macrolides and fluoroquinolones.

New approaches to optimizing antimicrobial therapy in patients with cystic fibrosis.

Chronic pulmonary infections are a significant cause of morbidity and mortality in patients with cystic fibrosis. The traditional approach to managing patients with cystic fibrosis is to treat acute exacerbations with antimicrobial, airway clearance, and nutritional therapies. Advances in the understanding of the pharmacodynamics of antibiotics have led to the development of new dosing strategies to maximize the antibiotics' activity. Recent data on the use of aerosolized tobramycin as chronic maintenance therapy have demonstrated that it improves pulmonary function significantly and reduces hospitalization days. New insights into the pathogenesis of pulmonary disease have led to the development of novel therapies, including salt-insensitive antimicrobial peptides and rBPI21, as adjunctive therapy to increase the sensitivity of current antibiotics. In addition, macrolide antibiotics are being investigated for their anti-inflammatory effects as chronic maintenance therapy. Until effective therapies are available to correct the basic genetic defect that causes cystic fibrosis, antibacterial and anti-inflammatory agents will continue to be the mainstay of treatment.

Unusual respiratory bacterial flora in cystic fibrosis: microbiologic and clinical features.

Pulmonary infections continue to be a significant source of morbidity and mortality among patients with cystic fibrosis. Although our understanding of the pathogenesis and clinical consequences of pulmonary infections with Pseudomonas aeruginosa has increased greatly in recent years, very little is known about potentially emerging pathogens such as Burkholderia cepacia complex, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and methicillin-resistant Staphylococcus aureus. In this review, the authors discuss methods for appropriate identification of these "unusual" organisms and their epidemiologic and clinical features. Multicenter surveillance studies are needed to more clearly establish the pathogenicity of these organisms.

Predictive performance of a vancomycin-aminoglycoside population model.

OBJECTIVE: To evaluate the Wragge-Cooper method of predicting vancomycin serum concentrations utilizing knowledge of aminoglycoside pharmacokinetic parameters in general medicine and intensive care unit populations, and to develop a revised model if necessary. DESIGN: This study consists of two phases evaluating 50 adults receiving concurrent vancomycin and aminoglycoside therapy. Patients were identified by a retrospective review of medical records. Bayesian analysis of measured serum aminoglycoside and vancomycin concentrations was performed to determine the individualized pharmacokinetic parameters. Phase I of the study tested the predictive performance of a published model incorporating aminoglycoside elimination (Wragge-Cooper) in 25 patients (group 1), and a revised model was developed. Phase II determined the predictive performance of the revised model (revised) and its performance relative to the Wragge-Cooper model and a traditional model incorporating estimated creatinine clearance (traditional) in an additional 25 patients (group 2). SETTING: Two tertiary care university teaching hospitals. MAIN OUTCOME MEASURES: The predictive performance of the models was determined by comparing predicted with measured vancomycin serum concentrations. Bias and precision were evaluated by calculating the mean prediction error (ME) and mean absolute error (MAE), respectively. Linear regression was performed to determine relationships between parameters. RESULTS: The Wragge-Cooper model consistently underpredicts vancomycin serum concentrations in general medicine and intensive care unit populations (ME = -5.18, MAE = 6.63). Relative predictive performance analysis indicates no significant difference in bias or precision between the traditional and Wragge-Cooper models (delta ME 1.17, delta MAE -0.80). Regression analysis of individualized aminoglycoside and vancomycin elimination derived from patients in group 1 reveals the following relationship: vancomycin k10 (1/h) = 0.081 + 1.037ke,amg, r = 0.73. The revised model is significantly less biased and more precise compared with the traditional model (delta ME -4.48; delta MAE 1.22), and is significantly less biased (delta ME 4.29) but no more precise than the Wragge-Cooper model (delta MAE -0.58), using patients from group 2. CONCLUSIONS: The revised model is an accurate method of predicting vancomycin serum concentrations in both general medicine and intensive care unit populations. Use of this model enables individualization of vancomycin dosage in patients receiving concurrent aminoglycoside therapy and minimizes vancomycin serum concentration monitoring.

Estimation of creatinine clearance in patients with metastatic ovarian cancer.

The authors evaluated the predictive performance of four methods used to estimate creatinine clearance (Cl(cr)) in patients with metastatic ovarian cancer. Methods described by Cockcroft and Gault, Jelliffe, and two equations derived from cancer patients by Robinson and Tsubaki, were evaluated. Estimated Cl(cr) values obtained by each method using actual weight (ABW), ideal weight (IBW) and lower of ABW and IBW were compared with measured values determined by a 12- or 24-hour urine collection for 14 patients enrolled in a controlled clinical trial. The mean prediction errors (ME) and mean absolute errors (MAE) were calculated to evaluate the bias and precision, respectively, of each method. The relationship between predicted and measured Cl(cr) is poor (r = 0.38 to 0.54). Cockcroft and Gault using ABW (p = 0.21), Robinson using ABW (p = 0.44), and Jelliffe (p = 0.17) were equally unbiased predictors of measured Cl(cr). All other methods significantly underestimated measured Cl(cr). All methods appeared to be equally imprecise (p<0.05). The use of standard equations for estimating Cl(cr) in patients with ovarian cancer is predictive of the measured 24-hour value. The use of oncology specific equations does not improve the accuracy or precision of these estimates.

Pharmacokinetics of tobramycin in adults with cystic fibrosis: implications for once-daily administration.

Once-daily administration of aminoglycosides is routinely used in many institutions. However, comparative efficacy data for patients with cystic fibrosis (CF) are lacking. The purpose of the present study was to compare the predicted pharmacodynamic activity of tobramycin at 10 mg/kg of body weight/day administered every 24 h (q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of data on the drug concentration in sera from 60 adult CF patients. Individual maximum a posteriori probability Bayesian PK parameter values were used to construct serum concentration-versus-time curves and to determine various indices (peak concentration/MIC ratio [peak/MIC], area under the concentration-time curve/MIC ratio [AUC/MIC], and time that the concentration was less than the MIC [T

Distribution and elimination of tobramycin administered in single or multiple daily doses in adult patients with cystic fibrosis.

Aminoglycosides are often prescribed as part of the treatment regimen for acute pulmonary exacerbations due to their potent activity and low potential for development of resistance. Preliminary evidence from randomized controlled trials in patients with cystic fibrosis (CF) suggests that once-daily administration of aminoglycosides results in similar efficacy and a low risk for toxicity compared with traditional dosing. The pharmacokinetics of aminoglycosides administered once daily in CF patients are currently not well described. In this study we compare the distribution and elimination patterns of traditional dosing (3.3 mg/kg q8h) versus once-daily dosing (10 mg/kg q24h) of tobramycin in six adult patients with CF. The pharmacokinetics of tobramycin administered either once daily or every 8 h were best described by a two-compartment model. No statistically significant differences in any of the pharmacokinetic parameter values between regimens were noted. The distribution phase half-lives of 32 and 24 min following the q8h and q24h regimens were longer than expected. The use of a one-compartment model requires clinical peak levels to be drawn 2 h after initiation of either a 30 min infusion for multiple daily dosing or a 60 min infusion with once-daily dosing, to ensure completion of the distribution phase. Our data indicate that a dose of 10 mg/kg/day provides post-distributional phase peak concentrations that achieve the desired goal for susceptible organisms (>20 mg/L) and AUC(24) values at the upper end of the desired range (70-100 mg.h/L).

Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis.

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 >or=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 from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC(0-24)/MIC ratio of >or=125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at alpha phase, 0.16 h; and half-life at beta phase, 2.9 h. The overall fractional attainment of achieving an AUC(0-24)/MIC ratio of >or=125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 microg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC(0-24)/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC(0-24)/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.