Disposition and metabolism of [14C]PTZ601 in healthy volunteers
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Flarakos, Jimmy, Ting, Lillian, Du, Yancy, Stein, Daniel, Reynolds, Christine, Patel, Manish, Roy, Sandip and Mangold, James (2012) Disposition and metabolism of [14C]PTZ601 in healthy volunteers. Xenobiotica. ISSN 0049-8254
Abstract
PTZ601 (razupenem) is a novel investigational carbapenem antibiotic with an antimicrobial spectrum of activity that includes pathogens responsible for community-acquired bacterial infections as well as multidrug-resistant Gram-positive pathogens. The purpose of this study was to assess the absorption, distribution, metabolism and elimination of [14C]PTZ601 in humans, and to identify metabolites found after its dosing.
Six healthy male subjects were enrolled in this open-label study. Subjects were given a single dose of 500 mg of [14C]PTZ601 (mean radioactivity 79.2 µCi) by intravenous (IV) infusion over one hour, and observed for five days post-dose during which pharmacokinetic (PK) samples (plasma, urine and feces) were collected. Plasma PTZ601 concentrations were determined using LC-MS/MS; PK parameters were estimated by non-compartmental analysis. Excretion and mass balance were determined with liquid scintillation analysis, and metabolites in PK samples were characterized by HPLC online radiochemical detection. Metabolite identification was performed by HPLC-high resolution mass spectrometry.
The single IV dose of PTZ601 was well tolerated. The disposition of PTZ601 was best described by a fast absorption, followed by a biphasic elimination phase. Peak PTZ601 plasma concentrations were reached within 0.5–1h. The mean elimination half-life was 1.6 h and the mean clearance was 13 L/h. Recovery of the radioactivity dose was complete (mean 92%). The main route of excretion (parent and metabolites) was the renal route, as urine accounted for 69-77%, while feces only 13-22%, of the total radioactivity. The majority of the drug was excreted in urine as multiple open ring metabolites: M17.3(oxidative ring-opened product) and M22.2 (di-cysteine conjugate of 17.3); unchanged PTZ601 in urine contributed to 15% of radioactivity. The major metabolites detected in plasma were M17.3, M12.8 (acetylated M17.3), M22.2, and M41.4 (methylated M17.3). PTZ601 was well tolerated. PTZ601 undergoes extensive metabolism to stable antimicrobially inactive metabolites before excretion via urine and feces.
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/7395 |