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Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers
Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting f...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112065/ https://www.ncbi.nlm.nih.gov/pubmed/36988461 http://dx.doi.org/10.1128/aac.01623-22 |
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author | Hodges, Michael R. Ople, Eric Wedel, Pamela Shaw, Karen J. Jakate, Abhijeet Kramer, William G. van Marle, Sjoerd van Hoogdalem, Ewoud-Jan Tawadrous, Margaret |
author_facet | Hodges, Michael R. Ople, Eric Wedel, Pamela Shaw, Karen J. Jakate, Abhijeet Kramer, William G. van Marle, Sjoerd van Hoogdalem, Ewoud-Jan Tawadrous, Margaret |
author_sort | Hodges, Michael R. |
collection | PubMed |
description | Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (C(max)) (SAD: 0.16 to 12.0 μg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 μg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 μg · h/mL). With single and repeat p.o., dose-proportional increases in C(max) (SAD: 1.30 to 6.41 μg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 μg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 μg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens. |
format | Online Article Text |
id | pubmed-10112065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-101120652023-04-19 Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers Hodges, Michael R. Ople, Eric Wedel, Pamela Shaw, Karen J. Jakate, Abhijeet Kramer, William G. van Marle, Sjoerd van Hoogdalem, Ewoud-Jan Tawadrous, Margaret Antimicrob Agents Chemother Experimental Therapeutics Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (C(max)) (SAD: 0.16 to 12.0 μg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 μg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 μg · h/mL). With single and repeat p.o., dose-proportional increases in C(max) (SAD: 1.30 to 6.41 μg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 μg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 μg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens. American Society for Microbiology 2023-03-29 /pmc/articles/PMC10112065/ /pubmed/36988461 http://dx.doi.org/10.1128/aac.01623-22 Text en Copyright © 2023 Pfizer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Experimental Therapeutics Hodges, Michael R. Ople, Eric Wedel, Pamela Shaw, Karen J. Jakate, Abhijeet Kramer, William G. van Marle, Sjoerd van Hoogdalem, Ewoud-Jan Tawadrous, Margaret Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers |
title | Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers |
title_full | Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers |
title_fullStr | Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers |
title_full_unstemmed | Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers |
title_short | Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers |
title_sort | safety and pharmacokinetics of intravenous and oral fosmanogepix, a first-in-class antifungal agent, in healthy volunteers |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112065/ https://www.ncbi.nlm.nih.gov/pubmed/36988461 http://dx.doi.org/10.1128/aac.01623-22 |
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