Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection
The increased prevalence of pulmonary methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection in patients living with cystic fibrosis (CF) is concerning due to a correlation with reduced life expectancy and lack of available treatment options. RV94 is a next generation lipogl...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/9/2250 |
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| author | Donna M. Konicek Adam J. Plaunt Sachin Gharse Sasha J. Rose Arielle Dorfman Amruta Sabnis Thomas Baker Helena Gauani Donald Chun Zhili Li Walter R. Perkins David Cipolla Vladimir S. Malinin |
| author_facet | Donna M. Konicek Adam J. Plaunt Sachin Gharse Sasha J. Rose Arielle Dorfman Amruta Sabnis Thomas Baker Helena Gauani Donald Chun Zhili Li Walter R. Perkins David Cipolla Vladimir S. Malinin |
| author_sort | Donna M. Konicek |
| collection | DOAJ |
| description | The increased prevalence of pulmonary methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection in patients living with cystic fibrosis (CF) is concerning due to a correlation with reduced life expectancy and lack of available treatment options. RV94 is a next generation lipoglycopeptide designed for pulmonary delivery that preclinically demonstrated high potency against MRSA in planktonic and protected colonies and improved pulmonary clearance relative to same class molecules. Here, RV94 was formulated into a dry powder for inhalation (DPI) to investigate the localized treatment of pulmonary MRSA presented in a potentially more convenient dosage form. RV94 DPI was generated using a spray-drying process with 12.5 wt% trileucine and demonstrated aerosol characteristics (2.0 μm MMAD and 73% FPF) predictive of efficient pulmonary deposition. In vivo PK from a single dose of RV94 DPI delivered by inhalation to rats yielded lung levels (127 μg/g) much greater than the MRSA minimum inhibitory concentration (0.063 μg/mL), low systemic levels (0.1 μg/mL), and a lung t<sub>1/2</sub> equal to 3.5 days. In a rat acute pulmonary MRSA model, a single dose of RV94 DPI delivered by inhalation either up to seven days prior to or 24 h after infection resulted in a statistically significant reduction in lung MRSA titer. |
| first_indexed | 2024-03-10T22:15:16Z |
| format | Article |
| id | doaj.art-489479d94ae3433599532bcbf80b551d |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T22:15:16Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-489479d94ae3433599532bcbf80b551d2023-11-19T12:27:06ZengMDPI AGPharmaceutics1999-49232023-08-01159225010.3390/pharmaceutics15092250Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA InfectionDonna M. Konicek0Adam J. Plaunt1Sachin Gharse2Sasha J. Rose3Arielle Dorfman4Amruta Sabnis5Thomas Baker6Helena Gauani7Donald Chun8Zhili Li9Walter R. Perkins10David Cipolla11Vladimir S. Malinin12Insmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAInsmed Incorporated, Bridgewater, NJ 08807, USAThe increased prevalence of pulmonary methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection in patients living with cystic fibrosis (CF) is concerning due to a correlation with reduced life expectancy and lack of available treatment options. RV94 is a next generation lipoglycopeptide designed for pulmonary delivery that preclinically demonstrated high potency against MRSA in planktonic and protected colonies and improved pulmonary clearance relative to same class molecules. Here, RV94 was formulated into a dry powder for inhalation (DPI) to investigate the localized treatment of pulmonary MRSA presented in a potentially more convenient dosage form. RV94 DPI was generated using a spray-drying process with 12.5 wt% trileucine and demonstrated aerosol characteristics (2.0 μm MMAD and 73% FPF) predictive of efficient pulmonary deposition. In vivo PK from a single dose of RV94 DPI delivered by inhalation to rats yielded lung levels (127 μg/g) much greater than the MRSA minimum inhibitory concentration (0.063 μg/mL), low systemic levels (0.1 μg/mL), and a lung t<sub>1/2</sub> equal to 3.5 days. In a rat acute pulmonary MRSA model, a single dose of RV94 DPI delivered by inhalation either up to seven days prior to or 24 h after infection resulted in a statistically significant reduction in lung MRSA titer.https://www.mdpi.com/1999-4923/15/9/2250DPIantibioticscystic fibrosisMRSAlipoglycopeptideinhalation |
| spellingShingle | Donna M. Konicek Adam J. Plaunt Sachin Gharse Sasha J. Rose Arielle Dorfman Amruta Sabnis Thomas Baker Helena Gauani Donald Chun Zhili Li Walter R. Perkins David Cipolla Vladimir S. Malinin Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection Pharmaceutics DPI antibiotics cystic fibrosis MRSA lipoglycopeptide inhalation |
| title | Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection |
| title_full | Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection |
| title_fullStr | Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection |
| title_full_unstemmed | Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection |
| title_short | Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection |
| title_sort | preclinical investigation of a lipoglycopeptide dry powder inhalation therapy for the treatment of pulmonary mrsa infection |
| topic | DPI antibiotics cystic fibrosis MRSA lipoglycopeptide inhalation |
| url | https://www.mdpi.com/1999-4923/15/9/2250 |
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