First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects

FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the ma...

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Vydané v:Antimicrobial agents and chemotherapy Ročník 68; číslo 1; s. e0133023
Hlavní autori: Huang, Zhiwei, Yang, Xinyi, Jin, Yi, Yu, Jicheng, Cao, Guoying, Wang, Jingjing, Hu, Yingying, Dai, Jingyi, Wu, Jufang, Wei, Qiong, Tian, Yan, Yu, Shuyan, Zhu, Xu, Mao, Xiaomeng, Liu, Wei, Liang, Hong, Zheng, Shansong, Ju, Yunfei, Wang, Zenghua, Zhang, Jing, Wu, Xiaojie
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 10.01.2024
Predmet:
Adult
Anti-Bacterial Agents - pharmacokinetics
beta-Lactamase Inhibitors - adverse effects
Healthy Volunteers
Humans
Infusions, Intravenous
Meropenem - pharmacology
FL058
β-lactamase inhibitor
target attainment analysis
first-in-human study
safety
population pharmacokinetics
ISSN:1098-6596, 1098-6596
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Abstract FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).
AbstractList FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).
FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).
Author Wang, Zenghua
Liang, Hong
Huang, Zhiwei
Wang, Jingjing
Wei, Qiong
Mao, Xiaomeng
Liu, Wei
Dai, Jingyi
Hu, Yingying
Yu, Shuyan
Tian, Yan
Jin, Yi
Wu, Jufang
Zhang, Jing
Yu, Jicheng
Zheng, Shansong
Yang, Xinyi
Zhu, Xu
Ju, Yunfei
Cao, Guoying
Wu, Xiaojie
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  organization: Phase I Clinical Research Center, Huashan Hospital, Fudan University , Shanghai, China
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  organization: Phase I Clinical Research Center, Huashan Hospital, Fudan University , Shanghai, China
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  organization: Phase I Clinical Research Center, Huashan Hospital, Fudan University , Shanghai, China
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  givenname: Shansong
  surname: Zheng
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  organization: Qilu Pharmaceutical Co. Ltd. , Jinan, China
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  surname: Wang
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  organization: Qilu Pharmaceutical Co. Ltd. , Jinan, China
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  orcidid: 0000-0002-0081-6507
  surname: Wu
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  organization: Phase I Clinical Research Center, Huashan Hospital, Fudan University , Shanghai, China
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crossref_primary_10_1016_j_addr_2024_115459
crossref_primary_10_1128_aac_01912_24
crossref_primary_10_3389_fmicb_2024_1516979
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β-lactamase inhibitor
target attainment analysis
first-in-human study
safety
population pharmacokinetics
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Snippet FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic...
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SubjectTerms Adult
Anti-Bacterial Agents - pharmacokinetics
beta-Lactamase Inhibitors - adverse effects
Healthy Volunteers
Humans
Infusions, Intravenous
Meropenem - pharmacology
Title First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects
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