Mass Balance and Pharmacokinetics of [14C]Telavancin following Intravenous Administration to Healthy Male Volunteers

ABSTRACT The mass balance and pharmacokinetics of telavancin, a semisynthetic lipoglycopeptide antimicrobial agent, were characterized in an open-label, phase 1 study of six healthy male subjects. After a single 1-h intravenous infusion of 10 mg/kg [14C]telavancin (0.68 μCi/kg), blood, urine, and feces were collected at regular intervals up to 216 h postdose. Whole blood, plasma, urine, and fecal samples were assayed for total radioactivity using scintillation counting; plasma and urine were also assayed for parent drug and metabolites using liquid chromatography with tandem mass spectrometry. The concentration-time profiles for telavancin and total radioactivity in plasma were comparable from 0 to 24 h after the study drug administration. Telavancin accounted for >95% and 83% of total radioactivity in plasma at 12 h and 24 h, respectively. By 216 h, approximately 76% of the total administered dose was recovered in urine while only 1% was collected in feces. Unchanged telavancin accounted for most (83%) of the eliminated dose. Telavancin metabolite THRX-651540 along with two other hydroxylated metabolites (designated M1 and M2) accounted for the remaining radioactivity recovered from urine. The mean concentrations of total radioactivity in whole blood were lower than the concentration observed in plasma, and mean concentrations of THRX-651540 in plasma were minimal relative to mean plasma telavancin concentrations. These observations demonstrate that most of an administered telavancin dose is eliminated unchanged via the kidneys. Intravenous telavancin at 10 mg/kg was well tolerated by all subjects.

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Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8557 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8557-8557

Author(s):

Hiroaki Akamatsu ◽

Hibiki Udagawa ◽

Kentaro Tanaka ◽

Masayuki Takeda ◽

Shintaro Kanda ◽

...

Keyword(s):

Phase 1 ◽

Study Drug ◽

Standard Of Care ◽

Japanese Patients ◽

Antibody Drug Conjugate ◽

Open Label ◽

Dose Escalation Study ◽

Open Label Phase ◽

Reported Study ◽

Third Line

8557 Background: SCLC rapidly recurs after first-line platinum therapy, and while several agents are approved in the relapsed/refractory setting, there is no approved agent or existing standard of care for third-line in Japan. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not in normal tissue. This was the first study evaluating safety, PK, and preliminary anti-tumor activity of Rova-T in Japanese pts. Methods: This was an open label Phase 1, 3+3 dose-escalation study of Rova-T in Japanese pts with advanced recurrent SCLC (NCT03086239). Eligibility: progressive disease after ≥2 prior systemic regimens incl. ≥1 platinum-based regimen; ECOG 0-1. Pts received 0.2 or 0.3 mg/kg Rova-T IV on Day 1 of a 6-week cycle for 2 cycles. Objective was to evaluate safety, tolerability, PK, and preliminary efficacy and expression of DLL3. Antitumor activity was measured by RECISTv1.1, and DOR, PFS, OS were evaluated. Results: 29 pts were treated with Rova-T (6 at 0.2mg/kg, 23 at 0.3 mg/kg). Median age 68 yrs; 76% male; 64% DLL3 high (≥75% expression); 86% DLL3 positive (≥25%). 20 pts (69%) had received ≥3 prior lines of therapy. Similar PK and AEs were seen compared to previous studies in non-Japanese pts. The most frequently reported study drug-related AEs were platelet count decreased, pleural effusion, oedema peripheral, and aspartate aminotransferase increased, the majority Grade 1/2. No DLTs occurred, and both dose levels were tolerated. Three pts previously treated with ≥3 prior lines of therapy had confirmed partial response by investigator (10% of all pts; 17% of DLL3 high pts). For DLL3 high pts, mDOR was 3.0 mos (95% CI: 2.9, 4.1), mPFS was 2.9 mos (1.2-3.6), and mOS was 7.4 mos (4.1-11.9). Individual responses were analyzed in detail and radiographic data with tumor shrinkage will be shown. Conclusions: Rova-T demonstrated a manageable safety profile with promising preliminary efficacy in Japanese SCLC pts, in particular pts with DLL3 high expression. These data support further exploration of Rova-T treatment in Japanese pts with SCLC in global Phase 3 studies. Clinical trial information: NCT03086239.

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Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of 14 C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers

Clinical Pharmacology in Drug Development ◽

10.1002/cpdd.376 ◽

2017 ◽

Vol 7 (2) ◽

pp. 207-216 ◽

Cited By ~ 6

Author(s):

Robert Townsend ◽

Kota Kato ◽

Christine Hale ◽

Donna Kowalski ◽

Christopher Lademacher ◽

...

Keyword(s):

Mass Balance ◽

Phase 1 ◽

Healthy Male ◽

Open Label ◽

Two Phase ◽

Healthy Male Volunteers ◽

Male Volunteers

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Pharmacokinetics, Mass Balance, and Metabolite Profiling of ODM-201 in Healthy Men: An Open-Label, Phase 1 Trial

10.26226/morressier.57d6b2bed462b8028d88ec73 ◽

2016 ◽

Author(s):

Christian Zurth

Keyword(s):

Mass Balance ◽

Metabolite Profiling ◽

Phase 1 ◽

Open Label ◽

Healthy Men ◽

Phase 1 Trial ◽

Open Label Phase

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Intravenously Administered Iduronate-2-Sulfatase Fused with Anti-Human Transferrin Receptor Antibody (Jr-141) Crosses the Blood-Brain Barrier to Address Central Nervous System Disorders in Hunter Syndrome: A Randomised, Open-Label, Phase 1/2 Trial

SSRN Electronic Journal ◽

10.2139/ssrn.3219534 ◽

2018 ◽

Author(s):

Torayuki Okuyama ◽

Yoshikatsu Eto ◽

Norio Sakai ◽

Kohtaro Minami ◽

Tatsuyoshi Yamamoto ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Blood Brain Barrier ◽

Transferrin Receptor ◽

Phase 1 ◽

Hunter Syndrome ◽

Open Label ◽

Central Nervous System Disorders ◽

Human Transferrin Receptor ◽

Open Label Phase

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A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01055-5 ◽

2021 ◽

Author(s):

Noboru Yamamoto ◽

Toshio Shimizu ◽

Kan Yonemori ◽

Shigehisa Kitano ◽

Shunsuke Kondo ◽

...

Keyword(s):

Liver Function ◽

Solid Tumors ◽

Dose Escalation ◽

Enzyme Inhibitor ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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