Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers
Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacok...
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| Veröffentlicht in: | Antimicrobial agents and chemotherapy 2019-01, Vol.63 (1) |
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| creator | O'Donnell, John Lawrence, Ken Vishwanathan, Karthick Hosagrahara, Vinayak Mueller, John P |
| description | Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (
) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was |
| doi_str_mv | 10.1128/AAC.01808-18 |
| format | Article |
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) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (
, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [
]) similar to that of the ascending dose study and a median
of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.).</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.01808-18</identifier><identifier>PMID: 30373802</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Adult ; Anti-Bacterial Agents ; Anti-Bacterial Agents - blood ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - urine ; Area Under Curve ; Barbiturates ; Barbiturates - blood ; Barbiturates - pharmacokinetics ; Barbiturates - urine ; Biological Availability ; Biotransformation ; Drug Administration Schedule ; Feces - microbiology ; Female ; Gastrointestinal Absorption - physiology ; Half-Life ; Healthy Volunteers ; Humans ; Male ; Pharmacology ; Spiro Compounds ; Spiro Compounds - blood ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - urine</subject><ispartof>Antimicrobial agents and chemotherapy, 2019-01, Vol.63 (1)</ispartof><rights>Copyright © 2018 American Society for Microbiology.</rights><rights>Copyright © 2018 American Society for Microbiology. 2018 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a418t-5036a7e0e203103041bf13ffccfd23e57bd663530383bf3a7139a4ad1ed196b03</citedby><cites>FETCH-LOGICAL-a418t-5036a7e0e203103041bf13ffccfd23e57bd663530383bf3a7139a4ad1ed196b03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325203/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325203/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30373802$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>O'Donnell, John</creatorcontrib><creatorcontrib>Lawrence, Ken</creatorcontrib><creatorcontrib>Vishwanathan, Karthick</creatorcontrib><creatorcontrib>Hosagrahara, Vinayak</creatorcontrib><creatorcontrib>Mueller, John P</creatorcontrib><title>Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (
) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (
, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [
]) similar to that of the ascending dose study and a median
of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.).</description><subject>Adult</subject><subject>Anti-Bacterial Agents</subject><subject>Anti-Bacterial Agents - blood</subject><subject>Anti-Bacterial Agents - pharmacokinetics</subject><subject>Anti-Bacterial Agents - urine</subject><subject>Area Under Curve</subject><subject>Barbiturates</subject><subject>Barbiturates - blood</subject><subject>Barbiturates - pharmacokinetics</subject><subject>Barbiturates - urine</subject><subject>Biological Availability</subject><subject>Biotransformation</subject><subject>Drug Administration Schedule</subject><subject>Feces - microbiology</subject><subject>Female</subject><subject>Gastrointestinal Absorption - physiology</subject><subject>Half-Life</subject><subject>Healthy Volunteers</subject><subject>Humans</subject><subject>Male</subject><subject>Pharmacology</subject><subject>Spiro Compounds</subject><subject>Spiro Compounds - blood</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - urine</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1PGzEQhq2KqqS0N87I10pZOl7vOt5LpSikgMSXROmhF8u7Oyamu3ZkbxD5B_xsHEJROXCaGc07z8zoJWSfwSFjufw-nc4OgUmQGZMfyIhBJTNRVmKHjACEyAoJxS75HOMdpLqs4BPZ5cAnXEI-Io_X1t12mB35iPRqoUOvG__XOhxsE8d0_tCElHo3ptq19BwHXfvOxp56Q_-kzHS-1Y3d9OmFv8eOXi9t8Mt1sL1tN5yQppFO3WBr6xN1TK2jJ6i7YbGmv323cgNiiF_IR6O7iF9f4h65-Tn_NTvJzi6PT2fTs0wXTA5ZCVzoCQLmwBlwKFhtGDemaUybcywndSsEL9ODkteG6wnjlS50y7BllaiB75EfW-5yVffYNuiGoDu1TPfqsFZeW_W24-xC3fp7JXhepqUJMN4CmuBjDGheZxmojSMqOaKeHVFMJvm3rVzHPld3fhVceu897cH_t72C_9nFnwDKbpZ2</recordid><startdate>20190101</startdate><enddate>20190101</enddate><creator>O'Donnell, John</creator><creator>Lawrence, Ken</creator><creator>Vishwanathan, Karthick</creator><creator>Hosagrahara, Vinayak</creator><creator>Mueller, John P</creator><general>American Society for Microbiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20190101</creationdate><title>Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers</title><author>O'Donnell, John ; Lawrence, Ken ; Vishwanathan, Karthick ; Hosagrahara, Vinayak ; Mueller, John P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a418t-5036a7e0e203103041bf13ffccfd23e57bd663530383bf3a7139a4ad1ed196b03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Anti-Bacterial Agents</topic><topic>Anti-Bacterial Agents - blood</topic><topic>Anti-Bacterial Agents - pharmacokinetics</topic><topic>Anti-Bacterial Agents - urine</topic><topic>Area Under Curve</topic><topic>Barbiturates</topic><topic>Barbiturates - blood</topic><topic>Barbiturates - pharmacokinetics</topic><topic>Barbiturates - urine</topic><topic>Biological Availability</topic><topic>Biotransformation</topic><topic>Drug Administration Schedule</topic><topic>Feces - microbiology</topic><topic>Female</topic><topic>Gastrointestinal Absorption - physiology</topic><topic>Half-Life</topic><topic>Healthy Volunteers</topic><topic>Humans</topic><topic>Male</topic><topic>Pharmacology</topic><topic>Spiro Compounds</topic><topic>Spiro Compounds - blood</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>O'Donnell, John</creatorcontrib><creatorcontrib>Lawrence, Ken</creatorcontrib><creatorcontrib>Vishwanathan, Karthick</creatorcontrib><creatorcontrib>Hosagrahara, Vinayak</creatorcontrib><creatorcontrib>Mueller, John P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>O'Donnell, John</au><au>Lawrence, Ken</au><au>Vishwanathan, Karthick</au><au>Hosagrahara, Vinayak</au><au>Mueller, John P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2019-01-01</date><risdate>2019</risdate><volume>63</volume><issue>1</issue><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (
) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (
, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [
]) similar to that of the ascending dose study and a median
of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.).</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>30373802</pmid><doi>10.1128/AAC.01808-18</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adult Anti-Bacterial Agents Anti-Bacterial Agents - blood Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - urine Area Under Curve Barbiturates Barbiturates - blood Barbiturates - pharmacokinetics Barbiturates - urine Biological Availability Biotransformation Drug Administration Schedule Feces - microbiology Female Gastrointestinal Absorption - physiology Half-Life Healthy Volunteers Humans Male Pharmacology Spiro Compounds Spiro Compounds - blood Spiro Compounds - pharmacokinetics Spiro Compounds - urine |
| title | Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers |
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