Anidulafungin

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James A. Dowell - One of the best experts on this subject based on the ideXlab platform.

  • in vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome p450 interactions of Anidulafungin
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Bharat Damle, Robert L Walsky, Gregory L Weber, Martin Stogniew, James A. Dowell, Philip B. Inskeep
    Abstract:

    Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of Anidulafungin. Experiments included in vitro degradation of Anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of Anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that Anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of Anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.

  • Pharmacokinetics and Tissue Distribution of Anidulafungin in Rats
    Antimicrobial agents and chemotherapy, 2008
    Co-Authors: Bharat Damle, Martin Stogniew, James A. Dowell
    Abstract:

    This study assessed the tissue distribution of Anidulafungin in rats. Anidulafungin rapidly distributed into tissues, achieving peak concentrations within 30 min, and maintained levels above MICs for common pathogens over 72 h. In tissues susceptible to fungal infection (liver, lung, spleen, kidney), exposure was 9- to 12-fold higher than in plasma.

  • Lack of pharmacokinetic interaction between Anidulafungin and tacrolimus.
    Journal of clinical pharmacology, 2007
    Co-Authors: James A. Dowell, Martin Stogniew, David Krause, Timothy Henkel, Bharat Damle
    Abstract:

    The safety and pharmacokinetics of Anidulafungin coadministered with tacrolimus were investigated using a single-sequence, open-label design. Healthy volunteers received 5 mg tacrolimus orally on days 1 and 13 of the study. Anidulafungin (200 mg) was administered intravenously on day 4, followed by 100-mg doses on days 5 through 13. Key pharmacokinetic parameters, including C(max), AUC, t((1/2)), CL, and V(ss), were derived from concentration-time data. The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of Anidulafungin plus tacrolimus to each drug alone were well within the 80% to 125% bioequivalence range, indicating no pharmacokinetic interaction. This ratio was 101.6 (90% CI: 92.77-111.22) for tacrolimus AUC(0-infinity) and 107.2 (90% CI: 105.1-109.4) for Anidulafungin AUC(ss). The 2 drugs were well tolerated, and no drug-related serious adverse events were reported. Because of its lack of pharmacokinetic interaction with key immunosuppressive agents, Anidulafungin is an important option for the prevention and treatment of invasive fungal infections in transplant recipients.

  • Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine
    Journal of clinical pharmacology, 2005
    Co-Authors: James A. Dowell, Martin Stogniew, David Krause, Timothy Henkel, Irving E. Weston
    Abstract:

    Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that Anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of Anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of Anidulafungin when concomitantly administered with cyclosporine. The potential for Anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H-cyclosporine with different concentrations of Anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of Anidulafungin were assessed in a multiple-dose, open-label clinical study of 12 healthy volunteers. Subjects received a 200-mg intravenous loading dose of Anidulafungin, followed by a daily 100-mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of Anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose-limiting toxicities or serious adverse events occurred. A small increase in Anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of Anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

  • Safety and Pharmacokinetics of Coadministered Voriconazole and Anidulafungin
    Journal of clinical pharmacology, 2005
    Co-Authors: James A. Dowell, Jennifer Schranz, Alice Baruch, Grover Foster
    Abstract:

    There is considerable interest in combining echinocandin and triazole antifungal agents for treatment of invasive fungal infections; however, information is needed regarding the tolerability and potential for pharmacokinetic interactions. Anidulafungin is a semisynthetic echinocandin, and voriconazole is an extended-spectrum triazole. In a random sequence, 17 subjects received Anidulafungin with placebo, voriconazole with placebo, and Anidulafungin with voriconazole. Anidulafungin was administered intravenously: 200 mg on day 1, then 100 mg/d on days 2 through 4. Voriconazole was administered orally: 400 mg every 12 hours on day 1, then 200 mg every 12 hours on days 2 to 4. No dose-limiting toxicities or serious adverse events occurred, and all adverse events were mild and consistent with the known safety profiles of both drugs. Pharmacokinetic parameters were not affected by coadministration. The geometric mean ratio (90% confidence interval) of the combination/drug alone for AUC S S was 97.4% (94.9-99.9), 97.4% (92.1-103.0), and 94.4% (87.0-102.5) for Anidulafungin, voriconazole, and the vonconazole metabolite, respectively.

Michael A Pfaller - One of the best experts on this subject based on the ideXlab platform.

  • use of Anidulafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 4 290 clinical isolates of candida by using clsi methods and interpretive criteria
    Journal of Clinical Microbiology, 2014
    Co-Authors: Michael A Pfaller, Daniel J. Diekema, Ronald N. Jones, S A Messer, Mariana Castanheira
    Abstract:

    This study addressed the application of Anidulafungin as a surrogate marker to predict the susceptibility of Candida to caspofungin due to unacceptably high interlaboratory variation of caspofungin MIC values. CLSI reference broth microdilution methods and species-specific interpretive criteria were used to test 4,290 strains of Candida (eight species), including 71 strains with documented fks mutations. Caspofungin MIC values were compared with those of Anidulafungin to determine the percentage of categorical agreement (CA) and very major (VME), major (ME), and minor error rates, as well as the ability to detect fks mutants. For all 4,290 isolates the CA was 97.1% (0.2% VME and ME, 2.5% minor errors) using Anidulafungin as the surrogate. Among the 62 isolates of Candida albicans (4 isolates), C. tropicalis (5 isolates), C. krusei (4 isolates), C. kefyr (2 isolates), and C. glabrata (47 isolates) that were nonsusceptible (NS; either intermediate [I] or resistant [R]) to both caspofungin and Anidulafungin, 52 (83.8%) contained a mutation in fks1 or fks2. Eight mutants of C. glabrata, two of C. albicans, and one each of C. tropicalis and C. krusei were classified as susceptible (S) to both antifungal agents. The remaining 7 mutants (2 C. albicans and 5 C. glabrata) were susceptible to one of the agents and either intermediate or resistant to the other. Using the epidemiological cutoff value (ECV) of 0.12 μg/ml for both caspofungin and Anidulafungin to differentiate wild-type (WT) from non-WT strains of C. glabrata, 42 of the 55 (76.4%) C. glabrata mutants were non-WT and 8 of the 55 (14.5%) were WT for both agents (90.9% concordance). Anidulafungin can accurately serve as a surrogate marker to predict S and R of Candida to caspofungin.

  • In vivo pharmacodynamic characterization of Anidulafungin in a neutropenic murine candidiasis model.
    Antimicrobial agents and chemotherapy, 2007
    Co-Authors: David R. Andes, Michael A Pfaller, Daniel J. Diekema, R. A. Prince, Karen Marchillo, J. Ashbeck, J. Hou
    Abstract:

    Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans , Candida tropicalis , and Candida glabrata infection to characterize the time course of activity of the new echinocandin Anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] to the MIC, and the ratio of the maximum serum drug concentration [ C max ] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal Anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum Anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max /MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max /MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans , C. tropicalis , and C. glabrata isolates with various Anidulafungin susceptibilities (MICs of Anidulafungin for these strains, 0.015 to 2.0 μg/ml) to determine if similar C max /MIC and AUC 0-24 /MIC ratios for these isolates were associated with efficacy. The Anidulafungin exposures associated with efficacy were similar among Candida species.

  • in vitro activities of Anidulafungin against more than 2 500 clinical isolates of candida spp including 315 isolates resistant to fluconazole
    Journal of Clinical Microbiology, 2005
    Co-Authors: Michael A Pfaller, Linda Boyken, S. Tendolkar, Shawn A. Messer, Richard J Hollis, Daniel J. Diekema
    Abstract:

    Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp. We assessed the in vitro activity of Anidulafungin against 2,235 clinical isolates of Candida spp. using the CLSI broth microdilution method. Anidulafungin was very active against Candida spp. (the MIC at which 90% of strains are inhibited [MIC90] was 2 μg/ml when MIC endpoint criteria of partial inhibition [MIC-2] were used). Candida albicans, C. glabrata, C. tropicalis, C. krusei, and C. kefyr were the most susceptible species of Candida (MIC90, 0.06 to 0.12 μg/ml), and C. parapsilosis, C. lusitaniae, and C. guilliermondii were the least susceptible (MIC90, 0.5 to 2 μg/ml). In addition, 315 fluconazole-resistant isolates were tested, and 99% were inhibited by ≤1 μg/ml of Anidulafungin. These results provide further evidence for the spectrum and potency of Anidulafungin activity against a large and geographically diverse collection of clinically important isolates of Candida spp.

  • Effectiveness of Anidulafungin in Eradicating Candida Species in Invasive Candidiasis
    Antimicrobial agents and chemotherapy, 2005
    Co-Authors: Michael A Pfaller, Linda Boyken, S. Tendolkar, Daniel J. Diekema, Shawn A. Messer, Richard J Hollis, B. P. Goldstein
    Abstract:

    In a phase 2 open-label, dose-ranging study in patients with candidemia, Anidulafungin was effective in eradicating Candida albicans and other species of Candida. The Anidulafungin MIC distribution showed that Candida albicans and C. glabrata were the most susceptible species and C. parapsilosis was the least susceptible species.

  • Anidulafungin: an echinocandin antifungal.
    Expert opinion on investigational drugs, 2004
    Co-Authors: Michael A Pfaller
    Abstract:

    Anidulafungin (LY-303366, V-echinocandin™, Vicuron Pharmaceuticals, Inc.) is a new echinocandin antifungal agent with broad spectrum activity against Candida and Aspergillus spp. Anidulafungin exhibits low toxicity, concentration-dependent fungicidal activity for Candida, and a prolonged post antifungal effect (> 12h). In vitro activity demonstrates excellent potency and spectrum versus azole-susceptible and -resistant Candida spp. and a low minimum effective concentration for Aspergillus spp. In vivo Anidulafungin is fungicidal against Candida in neutropenic animal models of disseminated candidiasis. Against Candida Anidulafungin exhibits concentration-dependent killing and clearance of residual fungal burden in target organs (liver, lung, spleen, kidney) and plasma/tissue concentrations exceed the minimum inhibitory and minimum fungicidal concentrations of the infecting organism throughout the dosing interval. Although the activity of Anidulafungin in animal models of pulmonary or disseminated aspergill...

Soňa Kucharikova - One of the best experts on this subject based on the ideXlab platform.

  • Anidulafungin increases the antibacterial activity of tigecycline in polymicrobial candida albicans staphylococcus aureus biofilms on intraperitoneally implanted foreign bodies
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: Ona Rogiers, Michelle Holtappels, Wafi Siala, Mohamed Lamkanfi, Francoise Van Bambeke, Katrien Lagrou, Patrick Van Dijck, Soňa Kucharikova
    Abstract:

    Objectives: We aimed to establish a novel murine intra-abdominal foreign body infection model to study the activity of anidulafung in and tigecycline against dual species Candida albicans/Staphylococcus aureus biofirrns. Methods: In vitro and in vivo single and dual species biofilms were developed inside serum-coated triple-lumen catheters placed in 24-well plates or implanted intraperitoneally in BALB/c mice. The effect of tigecycline and Anidulafungin alone and in combination was tested using clinically relevant concentrations. Scanning electron microscopy was used to visualize the mature biofilm structure developed intraperitoneally. Flow cytometry was used to determine the immunological response upon infection, Immunoblot analysis allowed us to determine the effect of Anidulafungin on poly-beta-(1,6)-N-acetylglucosamine in in vitro-grown S. aureus biofirms. Results: We determined the MIC, MBC and in vitro susceptibility profile for Anidulafungin and tigecycline against C. albicans and S. aureus in mixed and single species biofilms. We demonstrated that a nidulafungin acts synergistically when combined with tigecycline against in vivo intra-abdominal biofilms, Moreover, we reveal that a nidulafungin reduces the abundance of S. aureus poly-beta-(1,6)-N-acetylglucosamine. The influx of neutrophils is much increased when infected with mixed biofilms compared with single species biofilms. Conclusions: Currently, treatment of intra-abdominal infections, in particular polymicrobial catheter-associated peritonitis, is ineffective, To the best of our knowledge, this is the first study that provides insight into new possible options for treatment of C. albicans/S. aureus biofilms present in the abdominal cavity.

  • in vivo efficacy of Anidulafungin against mature candida albicans biofilms in a novel rat model of catheter associated candidiasis
    Antimicrobial Agents and Chemotherapy, 2010
    Co-Authors: Michelle Holtappels, Patrick Van Dijck, Soňa Kucharikova, Helene Tournu, Katrien Lagrou
    Abstract:

    The present study demonstrates the efficacy of Anidulafungin on mature Candida albicans biofilms in vivo. One hundred fifty-seven catheter fragments challenged with C. albicans were implanted subcutaneously in rats. After formation of biofilms, rats were treated with daily intraperitoneal injections of Anidulafungin for 7 days. Catheters retrieved from treated animals showed reduced cell numbers compared to those retrieved from untreated and fluconazole-treated animals. Systemic administration of Anidulafungin is promising for the treatment of mature C. albicans biofilms.

Jose A. Vazquez - One of the best experts on this subject based on the ideXlab platform.

  • differential in vitro activity of Anidulafungin caspofungin and micafungin against candida parapsilosis isolates recovered from a burn unit
    Clinical Microbiology and Infection, 2009
    Co-Authors: Mahmoud A Ghannoum, Jose A. Vazquez, A Chen, M Buhari, Jyotsna Chandra, Pranab K Mukherjee, D Baxa, A Golembieski
    Abstract:

    Recent studies suggest that differences in antifungal activity among echinocandins may exist. In this study, the activities of three echinocandins (Anidulafungin, caspofungin, and micafungin) against Candida parapsilosis isolates from burn unit patients, healthcare workers and the hospital environment were determined. Additionally, the effect of these echinocandins on the cell morphology of caspofungin-susceptible and caspofungin-non-susceptible isolates was assessed using scanning electron microscopy (SEM). The C. parapsilosis isolates obtained from patients were susceptible to Anidulafungin, but were less so to caspofungin and micafungin. Isolates obtained from healthcare workers or environmental sources were susceptible to all antifungals. SEM data demonstrated that although Anidulafungin and caspofungin were equally active against a caspofungin-susceptible C. parapsilosis strain, they differed in their ability to damage a caspofungin-non-susceptible strain, for which lower concentrations of Anidulafungin (1 mg/L) than of caspofungin (16 mg/L) were needed to induce cellular damage and distortion of the cellular morphology. To determine whether the difference in the antifungal susceptibility of C. parapsilosis isolates to Anidulafungin as compared to the other two echinocandins could be due to different mutations in the FKS1 gene, the sequences of the 493-bp region of this gene associated with echinocandin resistance were compared. No differences in the corresponding amino acid sequences were observed, indicating that differences in activity between Anidulafungin and the other echinocandins are not related to mutations in this region. The results of this study provide evidence that differences exist between the activities of Anidulafungin and the other echinocandins.

  • differential in vitro activity of Anidulafungin caspofungin and micafungin against candida parapsilosis isolates recovered from a burn unit
    Clinical Microbiology and Infection, 2009
    Co-Authors: Mahmoud A Ghannoum, Jose A. Vazquez, A Chen, M Buhari, Jyotsna Chandra, Pranab K Mukherjee, D Baxa, A Golembieski
    Abstract:

    Recent studies suggest that differences in antifungal activity among echinocandins may exist. In this study, the activities of three echinocandins (Anidulafungin, caspofungin, and micafungin) against Candida parapsilosis isolates from burn unit patients, healthcare workers and the hospital environment were determined. Additionally, the effect of these echinocandins on the cell morphology of caspofungin-susceptible and caspofungin-non-susceptible isolates was assessed using scanning electron microscopy (SEM). The C. parapsilosis isolates obtained from patients were susceptible to Anidulafungin, but were less so to caspofungin and micafungin. Isolates obtained from healthcare workers or environmental sources were susceptible to all antifungals. SEM data demonstrated that although Anidulafungin and caspofungin were equally active against a caspofungin-susceptible C. parapsilosis strain, they differed in their ability to damage a caspofungin-non-susceptible strain, for which lower concentrations of Anidulafungin (1 mg/L) than of caspofungin (16 mg/L) were needed to induce cellular damage and distortion of the cellular morphology. To determine whether the difference in the antifungal susceptibility of C. parapsilosis isolates to Anidulafungin as compared to the other two echinocandins could be due to different mutations in the FKS1 gene, the sequences of the 493-bp region of this gene associated with echinocandin resistance were compared. No differences in the corresponding amino acid sequences were observed, indicating that differences in activity between Anidulafungin and the other echinocandins are not related to mutations in this region. The results of this study provide evidence that differences exist between the activities of Anidulafungin and the other echinocandins.

  • Anidulafungin: an evidence-based review of its use in invasive fungal infections
    Core evidence, 2008
    Co-Authors: Susan L. Davis, Jose A. Vazquez
    Abstract:

    INTRODUCTION Anidulafungin is a new echinocandin antifungal agent with indications for use in esophageal candidiasis and candidemia. The mortality and morbidity associated with fungal infections in healthcare facilities necessitates the development of new treatment options for these diseases. AIMS This review assesses the pharmacology and evidence for the use of Anidulafungin in the treatment of serious fungal infections. EVIDENCE REVIEW There is substantial evidence that Anidulafungin is a potent antifungal agent with activity against a broad range of fungal species. Likewise, evidence supports that Anidulafungin is a well-tolerated antifungal agent. Clinical studies provide sufficient evidence for regulatory approval for esophageal candidiasis and candidemia, and limited evidence suggests that Anidulafungin may be superior to fluconazole for candidemia and invasive candidiasis. The introduction of Anidulafungin into clinical practice adds a third option for therapy in the echinocandin class. Research into its efficacy in other fungal infections is ongoing, and further studies into the impact of Anidulafungin on economic outcomes will be beneficial. PLACE IN THERAPY Current evidence supports the use of Anidulafungin in the management of candidemia, esophageal candidiasis, and invasive candidiasis, as demonstrated by the successful results in large multicenter clinical trials.

  • Anidulafungin: A Novel Echinocandin
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006
    Co-Authors: Jose A. Vazquez, Jack D. Sobel
    Abstract:

    Until recently, the treatment available for serious fungal infections was composed of amphotericin B and azoles, and each class demonstrated significant limitations. Echinocandins are a new class of drugs that have shown promising results in treating a variety of fungal infections. Of these, Anidulafungin is a novel echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It has potent in vitro activity against Aspergillus and Candida species, including those resistant to fluconazole or amphotericin B. Results of several clinical trials indicate that Anidulafungin is effective in treating esophageal candidiasis, including azole-refractory disease. The results of a recent study comparing fluconazole versus Anidulafungin demonstrated the superiority of Anidulafungin in the treatment of candidemia and invasive candidiasis (IC). Studies evaluating the concomitant use of Anidulafungin and either amphotericin B, voriconazole, or cyclosporine did not demonstrate significant drug-drug interactions or adverse events. To date, Anidulafungin appears to have an excellent safety profile. On the basis of early clinical experience, it appears that Anidulafungin will be a valuable asset in the management of serious and difficult-to-treat fungal infections.

  • Anidulafungin: a novel echinocandin
    Therapy, 2006
    Co-Authors: Jose A. Vazquez
    Abstract:

    Fungal infections have emerged as a major cause of morbidity and mortality in an immunocompromised host. Until recently, the available treatment for serious fungal infections comprised either amphotericin B or azoles, which have limitations. The development of the echinocandins, including caspofungin and micafungin, has helped to fill the need for more efficacious antifungals that are broad spectrum, useful across different patient populations and have a good safety profile. Anidulafungin is the newest of the echinocandins under development for the treatment of mucosal and systemic fungal infections. Anidulafungin has demonstrated potent in vitro activity against Aspergillus and Candida spp., including those strains that are resistant to either fluconazole or amphotericin B. Results of several clinical trials show that Anidulafungin is effective in treating esophageal candidiasis, candidemia and invasive candidiasis. In addition, studies evaluating the concomitant use of Anidulafungin and either amphotericin, voriconazole or cyclosporin did not show clinically significant drug–drug interactions or altered adverse event profiles. A population kinetics analysis showed no significant effect of age, race, concomitant medications and renal or hepatic insufficiency on the population kinetic properties of Anidulafungin. The efficacy and safety profile of Anidulafungin, combined with its unique pharmacokinetic characteristics, make it a suitable alternative antifungal compound for first-line therapy of candidemia as well as mucosal, systemic and antifungal-refractory candidiasis.

Ping Liu - One of the best experts on this subject based on the ideXlab platform.

  • Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis
    Antimicrobial agents and chemotherapy, 2014
    Co-Authors: Ping Liu, Diane R. Mould
    Abstract:

    To assess the pharmacokinetics (PK) of voriconazole and Anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and Anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or Anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; Anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or Anidulafungin. PK parameter estimates of voriconazole and Anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated Anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

  • Population Pharmacokinetic-Pharmacodynamic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis
    Antimicrobial agents and chemotherapy, 2014
    Co-Authors: Ping Liu, Diane R. Mould
    Abstract:

    To evaluate the exposure-response relationships for efficacy and safety of voriconazole and Anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and Anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n = 176]) and safety (hepatic [n = 238], visual [n = 199], and psychiatric [n = 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or Anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as Anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and Anidulafungin exposures (area under the curve [AUC] and trough concentration [Cmin]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and Cmin) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479).

  • Population Pharmacokinetic-Pharmacodynamic Analysis of Anidulafungin in Adult Patients with Fungal Infections
    Antimicrobial agents and chemotherapy, 2012
    Co-Authors: Ping Liu
    Abstract:

    To evaluate the exposure-response relationships for efficacy and safety of intravenous Anidulafungin in adult patients with fungal infections, a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from 262 patients in four phase 2/3 studies. The plasma concentration data were fitted with a previously developed population PK model. Anidulafungin exposures in patients with weight extremities (e.g., 40 kg and 150 kg) were simulated based on the final PK model. Since the patient population, disease status, and efficacy endpoints varied in these studies, the exposure-efficacy relationship was investigated separately for each study using logistic regression as appropriate. Safety data from three studies (n = 235) were pooled for analysis, and one study was excluded due to concomitant use of amphotericin B as a study treatment and different disease populations. The analysis showed that the same dosing regimen of Anidulafungin can be administered to all patients regardless of body weight. Nonetheless, caution should be taken for patients with extremely high weight (e.g., >150 kg). There was a trend of positive association between Anidulafungin exposure and efficacy in patients with esophageal candidiasis or invasive candidiasis, including candidemia (ICC); however, adequate characterization of the effect of Anidulafungin exposure on response could not be established due to the relatively small sample size. No threshold value for exposure could be established, since patients with low exposure also achieved successful outcomes (e.g., area under the curve < 40 mg · h/liter in ICC patients). There was no association between Anidulafungin exposure and the treatment-related adverse events or all-causality hepatic laboratory abnormalities.

  • Tissue Distribution of Anidulafungin in Neonatal Rats
    Birth defects research. Part B Developmental and reproductive toxicology, 2012
    Co-Authors: Sharon L. Ripp, Jalal A. Aram, Umberto Conte, Christopher J. Bowman, Gary W. Chmielewski, David M. Cross, Hongying Gao, Elise M. Lewis, Jian Lin, Ping Liu
    Abstract:

    Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated Anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with Anidulafungin (10 mg/kg) or once daily for 5 days (PND 4-8). Plasma and tissue samples were collected and Anidulafungin levels were measured by liquid chromatography-tandem mass spectrometry. The mean plasma Cmax and AUC0-24 values were consistent with single-dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone-to-plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3- to 1.8-fold. Brain concentrations were low after single dose, with brain-to-plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single-dose administration in both PND 4 and PND 8 animals, indicating that Anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, Anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues.