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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.).

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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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