Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints

OBJECTIVES: Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure–response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. METHODS: The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. RESULTS: Mean plasma isavuconazole AUC/MIC (EC(50)) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid E(max) curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC(80)) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment. CONCLUSIONS: The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents

Pharmacokinetics of a Pediatric Tribendimidine Dose-Finding Study To Treat Hookworm Infection in African Children

Tribendimidine is a broad-spectrum anthelminthic available in China, which is currently being pursued for U.S. Food and Drug Administration approval for soil-transmitted helminth infections. Pharmacokinetic (PK) studies with tribendimidine in children, the main target group for treatment programs, have not been conducted to date. In the framework of a dose-ranging study in hookworm-infected school-aged children in Côte d'Ivoire, children were treated with either 100, 200, or 400 mg tribendimidine. Dried blood spot samples were collected up to 22 h after treatment. The active metabolite, deacetylated amidantel (dADT) and its metabolite acylated dADT (adADT) were quantified using liquid chromatography tandem mass spectrometry. PK parameters were calculated using a noncompartmental model, and univariate logistic regression was applied using maximal blood concentrations (; C; max; ) and area under the blood concentration-time curve for 0 to 22 h (AUC; 0-22; ) as predictors of drug efficacy. Dried blood spot samples of 101 children were analyzed. We observed a less than proportional and proportional exposure in dADT's median; C; max; and AUC; 0-22; , respectively, following administration of 100 mg (; C; max; = 853 ng/ml; AUC; 0-22; = 3,019 h · ng/ml) and 400 mg (; C; max; = 2,275 ng/ml; AUC; 0-22; = 12,530 h · ng/ml) tribendimidine. There were large, dose-independent variations in the time to; C; max; (; T; max; ) and ratios of dADT to adADT. We did not detect an influence of; C; max; or AUC; 0-22; of dADT or adADT on drug efficacy or adverse events. Since our study population was bearing hookworm infection of mainly low intensity, additional studies with heavy intensity infections might be required to confirm this observation

Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

Isavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n = 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 for Aspergillus spp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 for Candida albicans (up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candida spp. (up to a MIC of 0.125 mg/liter). The estimations for Candida spp. were exploratory considering that no patients with Candida infections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.

Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT)

The Distribution, Metabolism, and Elimination of Clofarabine in Rats

Abstract The distribution, metabolism and elimination of intravenous 14C-clofarabine was studied in Fischer 344 male rats under a once daily for 5 days dosing schedule of 25 or 50 mg/kg/day. Also, the in vitro metabolism in rat, dog, and human hepatocytes was studied. Plasma radioactivity (of which clofarabine accounted for 63% to 93%) exhibited three phases of exponential elimination with half-lives of 0.3, 1.3, and 12.8 hours after administration of the 25 mg/kg/d regimen. Unscheduled deaths occurred after 1 to 3 doses with the 50 mg/kg regimen, possibly due to nonlinear pharmacokinetics, and so mass balance and radiokinetic profiles could not be obtained. A total of 77.1% (of which 87.2% was clofarabine) and 10.8% (of which 6.9% was clofarabine) of the dose was recovered in urine and feces, respectively. 6-ketoclofarabine, believed to be formed via adenosine deaminase, was the metabolite of greatest concentration found in urine and feces, but in each matrix accounted for only 7% of the daily recovery of radioactivity. 6-ketoclofarabine was also found in myocardium and liver, but accounted for less than 2% of the total radioactivity in those tissues. Clofarabine was the major analyte found in myocardium (> 97% region of integration) and liver (> 94% region of integration). Whole body autoradiography demonstrated that the highest postdistributive concentrations of radioactivity were in the excretory organs, kidney, bladder and GI tract, with no remarkable suborgan distribution. In rat, dog, and human hepatocytes, 95, 96, and 99.8%14C-clofarabine remained, respectively, after 6 hours incubation. Eleven metabolites were observed with the largest constituting 2.5% of the radioactivity