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Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens.

ABSTRACT: Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC_0-24ss), AUC/MIC, and time above the MIC during the dosing interval (T > MIC), while QTc prolongation was associated with the maximal concentration at steady state (C_maxss) in a thorough QTc phase 1 study. Using PK data collected from 470 patients from the previously conducted phase 3 complicated skin and skin structure infection (cSSSI) trials, population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC_0-24ss, AUC/MIC, and T > MIC while minimizing the probability of a C_maxss of ?800 ng/ml relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of body weight infused intravenously over 0.5 h every 12 h. The MCS analyses indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 28%, and 32% increases in AUC_0-24ss, AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a C_maxss of ?800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg iclaprim administered over 2 h every 12 h was selected as the dosing scheme for subsequent phase 3 clinical trials.

SUBMITTER: Lodise TP

PROVIDER: S-EPMC5786772 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens.

Lodise Thomas P TP Bosso John J Kelly Colleen C Williams Paul J PJ Lane James R JR Huang David B DB

Antimicrobial agents and chemotherapy 20180125 2

Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC<sub>0-24ss</sub>), AUC/MIC, and time above the MIC during the dosing interval (<i>T</i> > MIC), ...[more]

PMID: 29133566

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Project description:Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT>MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT>1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT>MIC, 50%) of >0.9 for MICs of ?16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.).

Project description:Background and objectiveIn the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients.MethodsThis was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed.ResultsOverall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (Vd) was 4.34 L, maximum elimination rate (Vmax) was 4.19 μg/day, and concentration at which the elimination pathway is half saturated (Km) was 0.22 μg/mL. Interindividual variability was identified for CL (18.9%) and Vd (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUCinf 1st DOSE) was 938 [±190] μg/mL*days. All patients had tocilizumab exposure above 1 μg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing.ConclusionsThis study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation.

Dataset Information

Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens.

Publications

Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens.

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