Phase 1 Safety, Tolerability and Pharmacokinetics of 3K3A-APC in Healthy Adult Volunteers

ABSTRACT Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing Escherichia coli. Shiga toxin type 2 (Stx2) is responsible for the renal toxicity that can follow intestinal infection and hemorrhagic colitis due to E. coli. A chimeric mouse-human antibody, designated cαStx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, cαStx2 was generally well tolerated. Pharmacokinetic studies indicated that clearance was stable over the dose range of 1.0 to 10 mg/kg of body weight (0.249 ± 0.023 ml/kg/h) but was higher for the 0.1-mg/kg dose (0.540 ± 0.078 ml/kg/h), suggesting saturable elimination. A similar nonlinear trend was observed for the volume of distribution, where average values ranged from 0.064 ± 0.015 liter/kg for the 1.0- to 10-mg/kg doses and 0.043 ± 0.005 for the 0.01-mg/kg dose. The relatively small volume of distribution suggests that the antibody is limited to the vascular (plasma) compartment. The mean half-life was 165 ± 66 h, with lowest values observed for the 0.1-mg/kg dose (56.2 ± 9.7 h) and the highest values reported for the 10.0-mg/kg dose (206.4 ± 12.4 h). Future studies are needed to confirm the safety of this cαStx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.

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Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00855-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 8

Author(s):

Amanda M. Healan ◽

J. McLeod Griffiss ◽

Howard M. Proskin ◽

Mary Ann O'Riordan ◽

Wesley A. Gray ◽

...

Keyword(s):

Steady State ◽

Healthy Adult ◽

Controlled Trial ◽

Phase 1 ◽

Plasma Concentrations ◽

Parameter Estimates ◽

Open Label ◽

Combination Drug ◽

Period 2 ◽

Adult Volunteers

ABSTRACT Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Mycobacterium tuberculosis. Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, n = 17) or rifampin (600 mg/day, n = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC0–336 approximately 45%, from 47.69 h·μg/ml in period 1 to 26.33 h·μg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.)

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First‐in‐Human Studies of MW01‐6‐189WH, a Brain‐Penetrant, Antineuroinflammatory Small‐Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers

Clinical Pharmacology in Drug Development ◽

10.1002/cpdd.795 ◽

2020 ◽

Author(s):

Linda J. Van Eldik ◽

Lumy Sawaki ◽

Karen Bowen ◽

Daniel T. Laskowitz ◽

Robert J. Noveck ◽

...

Keyword(s):

Small Molecule ◽

Healthy Adult ◽

Phase 1 ◽

Human Studies ◽

Drug Candidate ◽

Small Molecule Drug ◽

Adult Volunteers

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Phase 1 Trial of the Dengue Virus Type 4 Vaccine Candidate rDEN4Δ30-4995 in Healthy Adult Volunteers

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2009.09-0131 ◽

2009 ◽

Vol 81 (5) ◽

pp. 834-841 ◽

Cited By ~ 31

Author(s):

Peter F. Wright ◽

Anna P. Durbin ◽

Bhavin Thumar ◽

Brett A. McKinney ◽

Joseph E. Blaney ◽

...

Keyword(s):

Dengue Virus ◽

Virus Type ◽

Healthy Adult ◽

Vaccine Candidate ◽

Phase 1 ◽

Phase 1 Trial ◽

Adult Volunteers

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A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of V-7404 in Healthy Adult Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01029-21 ◽

2021 ◽

Author(s):

Martin K. Kankam ◽

Jennifer M. Burns ◽

Marc S. Collett ◽

Michael L. Corrado ◽

Jeffrey R. Hincks

Keyword(s):

Healthy Adult ◽

Clinical Laboratory ◽

Clinical Investigation ◽

Phase 1 ◽

Vital Signs ◽

Physical Examinations ◽

Electrocardiographic Findings ◽

Direct Acting ◽

Oral Doses ◽

Adult Volunteers

V-7404, a direct-acting enterovirus (EV) 3C protease inhibitor, is being developed as a treatment option for serious EV infections, including infections in immunodeficient people excreting vaccine-derived polioviruses. V-7404 may be combined with pocapavir (V-073), a capsid inhibitor, to treat these infections. A Phase 1 single ascending dose (SAD; N=36) and multiple ascending doses (MAD; N=40) study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of V-7404 in healthy adult volunteers following oral doses starting at 200 mg and escalating to 2000 mg once daily (QD) and 2000 mg twice daily (BID). Adverse events (AEs), vital signs, electrocardiographic findings, physical examinations, clinical laboratory values, and PK of blood samples were assessed. No notable differences in demographic and baseline characteristics were observed across the dose cohorts. A total of 35/36 participants (97.2%) completed the SAD study (1 withdrew in placebo group), and 37/41 participants (90.2%) completed the MAD study (1 withdrew from the 2000 mg QD and 3 withdrew from the 2000 mg BID cohorts). No serious AEs or deaths were reported. Treatment-emergent AEs were mild or moderate in severity. Oral doses of V-7404 in all cohorts were readily absorbed and showed no significant accumulation. PK exposure increased in an approximately dose proportional manner and appeared to be independent of time. Overall, V-7404 was well-tolerated and exhibited an acceptable safety and PK profile, supporting further clinical investigation of V-7404 for the treatment of serious EV infections.

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