Publications by authors named "Anne Schmitt-Hoffmann"

Background: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.

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Article Synopsis
  • BAL101553 is a prodrug showing broad anti-cancer effects in hard-to-treat tumor models, particularly those resisting traditional microtubule-targeting treatments.
  • A phase 1/2a clinical trial was conducted to establish the maximum tolerated dose (MTD) and assess safety and efficacy in adults with advanced solid tumors, with the MTD found to be 60 mg/m.
  • The recommended phase 2 dose (RP2D) for infusion was determined to be 30 mg/m, with a disease control rate of 26.3%, while side effects included reversible gait disturbances and asymptomatic myocardial injury at higher doses.
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Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity.

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Objective/methods: Two openlabel, single-dose, randomized crossover studies and one open-label, multiple-dose, parallel group study in healthy volunteers were conducted with the prodrug, isavuconazonium sulfate, to determine absolute bioavailability of the active triazole, isavuconazole (EudraCT 2007-004949-15; n = 14), and the effect of food (EudraCT 2007- 004940-63; n = 26), and pH (NCT02128893; n = 24) on the absorption of isavuconazole. Isavuconazonium sulfate 744 mg designed to deliver 400 mg of the active triazole isavuconazole was administered in the absolute bioavailability (oral or intravenous (IV) (2-hour infusion)) and food-effect studies (oral). In the pH-effect study, isavuconazonium sulfate 372 mg designed to deliver 200 mg of isavuconazole was administered orally three times daily (t.

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This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUC ) during a dosing interval by 90% and maximum concentration (C ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC ) and C by 422% and 9%, respectively.

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Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study.

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A systematic comparison between two labeling approaches for the investigation of the in vitro metabolic pattern of pharmaceutical drugs was performed by examining the use of (i) radiolabeled drugs analyzed with LC-MS-offline radiodetection and (ii) stable-isotope labeled drugs, used in a defined mixture with the unlabeled drug and analyzed by LC-MS with recognition of the specific isotopic pattern. (14)C was used for the radioisotope-approach and deuterium for the stable-isotope approach. Olanzapine, diclofenac and ketoconazole were chosen as model drugs, as they are commercially available in their non-, radio- and stable-isotope labeled forms.

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Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964).

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Objectives: Carbapenem resistance in Gram-negative bacteria, mediated by restricted net influx and carbapenem-hydrolysing β-lactamases, is a growing problem. The monosulfactam antibiotic BAL30072 is stable to most carbapenemases, suggesting that it could be complementary to carbapenems. We have investigated the antimicrobial activity of BAL30072 combined with imipenem, meropenem and doripenem.

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Article Synopsis
  • A new method was developed using enzyme inhibitors to study how certain prodrugs, like ceftobiprole medocaril (BAL5788), are converted in different biological environments, including plasma and various organs.
  • The study showed that the hydrolysis (breakdown) of the prodrug occurs rapidly across all tested tissues and isn't significantly affected by certain enzyme inhibitors, indicating that carboxylesterases are primarily responsible for this process instead of P450 enzymes.
  • The findings suggest that BAL5788 has multiple conversion pathways, making it less likely to be influenced by genetic differences or drug interactions that could alter enzyme activity.
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The DNA gyrase inhibitor cyclothialidine had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance to clinically used drugs. Bicyclic lactone derivatives containing in their 12-14-membered ring a thioamide functionality were reported previously to exhibit potent antibacterial activity against gram-positive bacteria. Moderate in vivo efficacy, however, was demonstrated only for derivatives bearing hydrophilic substituents, which were found to have a favorable impact on pharmcokinetics, and to reduce metabolic degradation, in particular glucuronidation.

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BAL30376 is a triple combination comprising a siderophore monobactam, BAL19764; a novel bridged monobactam, BAL29880, which specifically inhibits class C β-lactamases; and clavulanic acid, which inhibits many class A and some class D β-lactamases. The MIC(90) was ≤ 4 μg/ml (expressed as the concentration of BAL19764) for most species of the Enterobacteriaceae family, including strains that produced metallo-β-lactamases and were resistant to all of the other β-lactams tested. The MIC(90) for Stenotrophomonas maltophilia was 2 μg/ml, for multidrug-resistant (MDR) Pseudomonas aeruginosa it was 8 μg/ml, and for MDR Acinetobacter and Burkholderia spp.

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Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Moraxella catarrhalis, and Mycobacterium avium, though the compounds were less active against Haemophilus influenzae. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by dfrB, dfrA (S1 isozyme), dfrE, and folA were susceptible to the dihydrophthalazines, whereas DHFRs encoded by dfrG (S3 isozyme) and dfrF were not.

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The in vitro metabolic profile of BAL30630, an antifungal piperazine propanol derivative, which inhibits the 1,3-beta-D-glucansynthase, was investigated by incubation with microsomes of several species and with rat hepatocytes. For the spotting of the metabolites, mixtures of BAL30630 with a stable isotope (deuterium) labeled analogue were incubated. The metabolic pattern comprises several oxidized metabolites.

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  • The study evaluated how the antibiotic ceftobiprole is absorbed and distributed in bone tissue after being given to uninfected New Zealand White rabbits via subcutaneous injection.
  • Higher doses of ceftobiprole (80 mg/kg) showed proportional increases in serum exposure and effective distribution in bone compared to lower doses (20 mg/kg), without drug accumulation over time.
  • In a separate experiment on a rabbit model of osteomyelitis, ceftobiprole effectively reduced bacterial levels in infected bones more than other antibiotics tested, demonstrating its potential as a treatment option for resistant infections.
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  • Ceftobiprole is a newly developed broad-spectrum cephalosporin antibiotic effective against MRSA and other Gram-positive and Gram-negative bacteria.
  • It is administered as a prodrug, ceftobiprole medocaril, which is quickly converted to the active drug in the body and is mostly eliminated unchanged through the kidneys.
  • The drug shows low binding to plasma proteins, minimal metabolism in the liver, and achieves steady-state concentrations in the body within the first day of dosing, with some slight differences in exposure levels between genders.
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The in vitro metabolic pattern of BAL19403, a novel macrolide antibiotic, was investigated by capillary liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF-MS) in incubations with human microsomes. For the elucidation of the metabolic pathway, BAL19403 labeled with four deuterium atoms (D4) was used, and detection of metabolites performed using mixtures of the unlabeled (H4) BAL19403 and its D4 analogue (1:1) as substrate. All metabolites appeared with similar chromatographic behavior.

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Background: BAL8557 (WSA) is the water-soluble prodrug of the triazole BAL4815 with in vitro anti-Aspergillus activity. We compared the activity of oral BAL8557 with oral itraconazole, oral voriconazole and intravenous caspofungin in a temporarily neutropenic murine model of disseminated Aspergillus flavus.

Methods: Mice were immunosuppressed using cyclophosphamide, then infected.

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The metabolic profile of BAL4815, an antifungal azole drug, was determined using in vitro rat hepatocyte incubations and subsequent analysis by capillary LC-qTof-MS and MS/MS including accurate mass determination. For the detection of the metabolites, a mixture of the drug and its deuterium-labelled analogue was used for incubations. Metabolic stability of BAL4815 was high in cultured rat hepatocytes.

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BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815.

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BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.

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BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. Safety and pharmacokinetic data from a multiple-dose study with 16 healthy male volunteers are reported. Subjects were randomized to receive BAL5788 at 500 or 750 mg (as BAL9141 equivalents; n = 6 subjects per dose) or placebo (n = 2 subjects per dose).

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BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. We investigated the safety and pharmacokinetics of BAL5788 in a double-blind, single-ascending-dose study with 40 healthy male subjects. The subjects were randomized to receive placebo (n = 2 subjects per dose) or BAL5788 (n = 6 subjects per dose) as a 200-ml intravenous infusion over 30 min.

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In an effort to find novel semisynthetic macrolides with extended antibacterial spectrum and improved activity we prepared a series of compounds based on commercially available clarithromycin, a potent and safe antimicrobial agent of outstanding clinical and commercial interest. According to the literature, improvement of antibacterial activity of erythromycin type antibiotics can be achieved by introduction of fused heterocycles such as cyclic carbonates or carbamates at positions 11 and 12 (such as in telithromycin). In the course of the work presented here, a similar, hitherto unprecedented set of compounds bearing a five-membered lactone ring fused to positions 11 and 12 was prepared based on carbon-carbon bond formation via intramolecular Michael addition of a [(hetero)arylalkylthio]acetic acid ester enolate to an alpha,beta-unsaturated ketone as the key step.

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BAL9141, a new antimicrobial agent belonging to the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, is active against most gram-positive microorganisms, including methicillin-resistant variants (methicillin-resistant Staphylococcus aureus [MRSA] and methicillin-resistant Staphylococcus epidermidis [MRSE]), as well as against penicillin-resistant pneumococci (PRP) and many gram-negative microorganisms. BAL9141 is administered as the prodrug BAL5788, which is rapidly converted to BAL9141 by plasma esterases. Pharmacokinetic (PK) data obtained in a previous multiple ascending dose study were used to fit a population PK model to using the NPEM2 program, yielding PK parameter estimates and its covariance matrix for BAL9141.

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