Anidulafungin is an echinocandin with activity against Candida species and Aspergillus species. Adult dosages under study are 50 mg/day for esophageal candidiasis and 100 mg/day for invasive candidiasis and aspergillosis. Little is known, however, about the safety and pharmacokinetics of anidulafungin in children. A multicenter, ascending-dosage study of neutropenic pediatric patients was therefore conducted. Patients were divided into two age cohorts (2 to 11 years and 12 to 17 years) and were enrolled into sequential groups to receive 0.75 or 1.5 mg/kg of body weight/day. Blood samples were obtained following the first and fifth doses. Anidulafungin was assayed in plasma, and pharmacokinetic parameters were determined. Safety was assessed using National Cancer Institute (NCI) common toxicity criteria. Pharmacokinetic parameters were determined for 12 patients at each dosage (0.75 mg/kg/day or 1.5 mg/kg/day). Concentrations and drug exposures were similar for patients between age cohorts, and weight-adjusted clearance was consistent across age. No drugrelated serious adverse events were observed. One patient had fever (NCI toxicity grade of 3), and one patient had facial erythema, which resolved with slowing the infusion rate. Anidulafungin in pediatric patients was well tolerated and can be dosed based on body weight. Pediatric patients receiving 0.75 mg/kg/day or 1.5 mg/kg/day have anidulafungin concentration profiles similar to those of adult patients receiving 50 or 100 mg/day, respectively.Anidulafungin is a novel antifungal agent of the echinocandin class with activity against Candida and Aspergillus species (2, 3, 6, 8, 9, 11-15, 18, 19). This drug has been studied with adult patients at dosages ranging from 50 to 100 mg/day for the treatment of esophageal candidiasis, invasive candidiasis, and candidemia, where it has been demonstrated to be well tolerated (4,5). A population pharmacokinetic analysis of plasma samples from 225 adult patients treated with anidulafungin demonstrated a two-compartment model with first-order elimination kinetics (5). Weight and gender are covariates in this model but have only a small impact on the plasma concentrations of anidulafungin. Dose modifications because of weight or gender differences in adults are therefore not required for anidulafungin (5). Although much is known about the pharmacokinetic properties of anidulafungin in adults, very little information regarding its properties in pediatric patients is known.Among the immunocompromised pediatric patients at high risk for development of invasive fungal infections are hospitalized children who have become neutropenic as a result of chemotherapy or other therapeutic interventions, such as hematopoietic stem cell transplantation (1, 18).The present study was conducted to assess the safety, tolerability, and pharmacokinetics of anidulafungin administered empirically to neutropenic children at high risk for invasive mycoses. MATERIALS AND METHODSObjectives and study design. This was a multicenter, open-label, dosageesc...
The pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (T max ) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (C max ) ranged from 0.0223 g/ml to 19.647 g/ml, and the area under the concentration-versus-time curve from time zero to time t (AUC 0-t ) ranged from 0.0402 g ⅐ h/ml to 28.599 g ⅐ h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (C max,ss ) ranged from 0.248 to 1.50 g/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUC ) ranged from 2.310 to 18.41 g ⅐ h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. Median T max values remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with its in vitro potency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.
b Solithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intentto-treat (ITT) (84.6% for solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for solithromycin; 5.9% for levofloxacin), and vomiting (0% for solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.)
The steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. (4,5,7,9,10,18,21). Solithromycin is also active against atypical respiratory pathogens such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila (4,13,18,20). Because of this in vitro spectrum of activity, solithromycin is currently being developed as monotherapy for the treatment of community-acquired bacterial pneumonia (CABP), and a phase 2 clinical trial of solithromycin for this indication has recently been completed (20) (NCT01168713; ClinicalTrials.gov).Information about anti-infective drug concentrations in the extracellular and intracellular compartments of the lung is essential for development of a drug for lower respiratory tract infections (1, 14). The intrapulmonary concentrations of newer macrolides (e.g., clarithromycin and azithromycin) and ketolides (e.g., telithromycin and cethromycin) have been reported to be consistently higher than those in plasma and are responsible, in part, for the effectiveness of these agents in the treatment of extracellular and intracellular pathogens associated with lower respiratory tract infections (3,6,(14)(15)(16). The goals of this study were to determine and compare the plasma and intrapulmonary concentrations of solithromycin in healthy, nonsmoking, adult subjects after multiple daily doses of 400 mg.(This work was presented in part at the Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, September 2010.) MATERIALS AND METHODSStudy design and subjects. This was a phase I, multiple-dose, open-label pharmacokinetic study in 30 healthy adults, including male and female subjects. The protocol was approved by the Quorum Review and University of Illinois at Chicago Institutional Review Boards. Healthy subjects between the ages of 18 and 55 years were enrolled into this study after written informed consent was obtained. All subjects were required to have a baseline medical history, physical examination, laboratory evaluation, and electrocardiogram (ECG) within 2 weeks (screening visit) and within 3 days (baseline) prior to solithromycin administration. All subjects had a body mass index of between 18 and 32 kg/m 2 , inclusive. Female subjects with childbearing potential were required to use one of the protocoldefined acceptable birth control methods before and during solithromycin administration and for 30 days following the last dose of solithromycin. Male subjects were also r...
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