Safety, Pharmacokinetics, and Drug-Drug Interaction Potential of Intravenous Durlobactam, a β-Lactamase Inhibitor, in Healthy Subjects

ABSTRACT Durlobactam (DUR; also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a cohort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0.25 to 8 g. In part B, multiple ascending doses of DUR ranging from 0.25 to 2 g were administered every 6 h (q6h) for 29 doses. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI-CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. After single and multiple doses, DUR demonstrated linear dose-proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug-drug interaction potential between DUR and SUL and/or IMI-CIL was identified. SUL-DUR at 1 g (of each component) administered q6h with a 3-h intravenous (i.v.) infusion is under development for the treatment of serious infections due to A. baumannii. (This study has been registered at ClinicalTrials.gov under identifier NCT02971423.)

Download Full-text

Evaluation of Drug–Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects

Clinical Drug Investigation ◽

10.1007/s40261-018-0697-2 ◽

2018 ◽

Vol 38 (11) ◽

pp. 1053-1060 ◽

Cited By ~ 13

Author(s):

Nao Kawaguchi ◽

Hiroki Koshimichi ◽

Toru Ishibashi ◽

Toshihiro Wajima

Keyword(s):

Drug Interaction ◽

Interaction Potential ◽

Healthy Subjects ◽

Drug Drug Interaction

Download Full-text

Clinical Drug-Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects

Clinical and Translational Science ◽

10.1111/cts.12557 ◽

2018 ◽

Vol 11 (5) ◽

pp. 477-486 ◽

Cited By ~ 5

Author(s):

Yasuyuki Ishii ◽

Yuko Ito ◽

Shunji Matsuki ◽

Kasumi Sanpei ◽

Osamu Ogawa ◽

...

Keyword(s):

Drug Interaction ◽

Interaction Potential ◽

Healthy Subjects ◽

Drug Drug Interaction ◽

Clinical Drug

Download Full-text

Pomalidomide: Evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects

The Journal of Clinical Pharmacology ◽

10.1002/jcph.384 ◽

2014 ◽

Vol 55 (2) ◽

pp. 168-178 ◽

Cited By ~ 19

Author(s):

Claudia Kasserra ◽

Mahmoud Assaf ◽

Matthew Hoffmann ◽

Yan Li ◽

Liangang Liu ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Interaction Potential ◽

Healthy Subjects ◽

Drug Drug Interaction

Download Full-text

Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

Clinical and Translational Science ◽

10.1111/cts.13118 ◽

2021 ◽

Author(s):

Ashit Trivedi ◽

Winnie Sohn ◽

Priyanka Kulkarni ◽

Pegah Jafarinasabian ◽

Hanze Zhang ◽

...

Keyword(s):

Drug Interaction ◽

Clinical Study ◽

Interaction Potential ◽

Healthy Subjects ◽

Pharmacokinetic Model ◽

Physiologically Based Pharmacokinetic Model ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based ◽

Omecamtiv Mecarbil ◽

Drug Drug Interaction

Download Full-text

Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects

European Journal of Clinical Pharmacology ◽

10.1007/s00228-020-03004-w ◽

2020 ◽

Author(s):

Allison Gaudy ◽

Christian Atsriku ◽

Ying Ye ◽

Kimberly MacGorman ◽

Liangang Liu ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Interaction Potential ◽

Healthy Subjects ◽

Phase 1 ◽

Phase 1 Study ◽

Drug Drug Interaction

Download Full-text

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug–Drug Interaction Study

Clinical and Translational Science ◽

10.1111/cts.12646 ◽

2019 ◽

Vol 12 (5) ◽

pp. 513-518 ◽

Cited By ~ 1

Author(s):

Naoyuki Otani ◽

Hirokazu Wakuda ◽

Hiromitsu Imai ◽

Masae Kuranari ◽

Yasuyuki Ishii ◽

...

Keyword(s):

Drug Interaction ◽

Healthy Subjects ◽

Interaction Study ◽

Drug Interaction Study ◽

Drug Drug Interaction ◽

Clinical Drug

Download Full-text

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug–drug interaction potential

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-012-1996-6 ◽

2012 ◽

Vol 71 (1) ◽

pp. 193-202 ◽

Cited By ~ 12

Author(s):

Patricia M. LoRusso ◽

Sarina A. Piha-Paul ◽

Monica Mita ◽

A. Dimitrios Colevas ◽

Vikram Malhi ◽

...

Keyword(s):

Drug Interaction ◽

Oral Contraceptive ◽

Solid Tumors ◽

Interaction Potential ◽

Locally Advanced ◽

Combined Oral Contraceptive ◽

Pharmacokinetic Assessment ◽

Drug Drug Interaction

Download Full-text

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00568-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 6326-6332 ◽

Cited By ~ 42

Author(s):

David C. Griffith ◽

Jeffery S. Loutit ◽

Elizabeth E. Morgan ◽

Stephanie Durso ◽

Michael N. Dudley

Keyword(s):

Plasma Clearance ◽

Healthy Adult ◽

Phase 1 ◽

High Dose ◽

Double Blind ◽

Time Curve ◽

Content Type ◽

Multiple Doses ◽

To Receive ◽

Lactamase Inhibitor

ABSTRACTVaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmaxand area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0–∞) was 144.00 ± 13.90 mg · h/liter, and theVsswas 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistantEnterobacteriaceae(CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.)

Download Full-text