Safety, Tolerability and PK 3-Period Crossover Study Comparing 2 Single Doses of ZTI-01 and Monurol® in Healthy Subjects

NCT02178254 | Completed Phase 1

• 2 other identifiers: 13-0064HHSN272201500005I
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The objective is to determine the safety, tolerability and pharmacokinetics (PK) of 2 single doses of ZTI-01 (1g and 8g infused over 1-hr) and a single dose of the Reference Label Drug, Monurol® (oral sachet, 3g). Subjects will be randomized to a treatment sequence prior to dosing on Day 1 of Period 1 prior to study screening.

Conditions

Pseudomonas Infection

Keywords

Pseudomonas aeruginosa, ZTI-101, phosphonic acid derivative, Monurol, fosfomycin tromethamine

Outcome Measures

Primary Outcomes (4)

• Pharmacokinetics: Maximum measured plasma concentration (Cmax), area under the concentration versus time curve (AUC0-t and AUC0-inf), time to peak concentration (tmax), terminal elimination half-life (t1/2), terminal-phase elimination rate constant).

  Study periods 1, 2 and 3, Day 1 through Day 3

• Pharmacokinetics: Volume of distribution (Vd) or apparent volume of distribution (Vd/F) as appropriate, clearance (CL) or apparent Clearance (CL/F) as appropriate, renal Clearance (CLr) and Fraction Bioavailable as appropriate

  Study periods 1, 2 and 3, Day 1 through Day 3

• Adverse events (AEs) will be monitored and recorded

  Study periods 1, 2 and 3, screening through Day 3, including washout periods

• Assessed safety and tolerability via physical examinations, vital signs, standard 12-lead electrocardiograms, and clinical laboratory tests

  Study periods 1, 2 and 3, screening through Day 3

Study Arms (3)

Sequence 3

EXPERIMENTAL

N=10 subjects receive 3grams oral sachet of Monurol in Period 1; 1.0gram of Intravenous (IV) ZTI-01 for Period 2 (1-hour infusion); and 8.0 grams IV ZTI-01 for Period 3.

Drug: Fosfomycin tromethamine; Drug: Fosfomycin disodium

Sequence 1

EXPERIMENTAL

N=10 subjects receive 1.0gram of Intravenous (IV) ZTI-01 for Period 1 (1-hour infusion); 8.0 grams IV ZTI-01 for Period 2 (1-hour infusion); and 3grams oral sachet of Monurol in Period 3.

Drug: Fosfomycin tromethamine; Drug: Fosfomycin disodium

Sequence 2

EXPERIMENTAL

N=10 subjects receive 8.0 grams IV ZTI-01 for Period 1(1-hour infusion); 3grams oral sachet of Monurol in Period 2 and 1.0gram of IV ZTI-01 for Period 3 (1-hour infusion)

Drug: Fosfomycin tromethamine; Drug: Fosfomycin disodium

Interventions

Fosfomycin tromethamine DRUG

A phosphonic acid derivative is the mono-acid salt of Fosfomycin with Tromethamine. Sequence 1-3 receive 3 grams oral sachet

Sequence 1; Sequence 2; Sequence 3

Fosfomycin disodium DRUG

ZTI-01 is a phosphonic acid derivative formulated as a disodium salt intravenous formulation. ZTI-01 acts by inhibiting peptidoglycan assembly, thereby disrupting cell wall synthesis. Sequence 1-3 receive 1 gram and 8 grams of Intravenous ZTI-01 for 1-hour infusion

Sequence 1; Sequence 2; Sequence 3

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy men and women from 18 to 45 years of age with no clinically significant findings on medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG) or clinical laboratory evaluation that were performed at Screening and Day -1.
• Body Mass Index (BMI) between 18-30 kg/m\^2, inclusive; and a total body weight \> 50 kg (110 lbs).
• Post-menopausal women with amenorrhea for at least 2 years with an FSH in the post-menopausal range as well as surgically sterile women (documented history of oophorectomy and/or hysterectomy, tubal ligation or tubal occlusion) will be eligible.
• Females of childbearing potential must use an acceptable birth control method (e.g., condom plus spermicide, combined oral contraceptive, implant, injectable, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) throughout the study and for 4 weeks following initiation of dosing with study drug.
• Male subjects must either had a vasectomy or agree to use a double barrier method of contraception, condom plus spermicide (or diaphragm plus spermicide in female partner) from the time of dosing with the study drug in Period 1 through 4 weeks following initiation of dosing with study drug.
• Nicotine-free by history (cigarettes, pipe, cigar, chewing tobacco, nicotine patch) for at least 30 days before Day -1 and urine cotinine at pre-study screening and Day -1 \<400 ng/mL).
• Able to abstain from grapefruit, grapefruit juice, grapefruit-containing products or alcoholic beverages within 48 hours before Day -1 and throughout the inpatient period.
• Willing to remain in the study facility and agree to abide to the Quintiles Phase 1 Unit House Rules for the duration of the inpatient study period.
• Have a high probability for compliance and completion of the study.
• Sign a dated, witnessed, written informed consent form

You may not qualify if:

• Subjects must meet none of the following study criteria at Study Day -1, Period 1:
• History or presence of any psychiatric or emotional disorder that might prevent the successful completion of the study.
• Any history or presence of clinically significant allergic conditions (e.g., recurrent dermatitis or drug hypersensitivity reactions).
• Have cancer or have a history of cancer (with exceptions of a few types of cancer, e.g. recent removal of basal cell skin carcinoma) within the past five years.
• Irritable bowel syndrome or any gastrointestinal disease (including frequent nausea due to migraine) within 30 days prior to study day 1, Period 1.
• History or presence of lactose intolerance.
• History of alcohol abuse within 12 months of study day 1, Period 1.
• History of intolerance or hypersensitivity to phosphonic acid derivative antibiotics or any of its constituents
• Use of any prescription drugs within 30 days of administration of the study drug
• Involvement in other investigational studies of any type (drugs, devices, procedures) within 30 days of screening.
• Blood or blood products donation within 60 days of Day -1.
• Use of any non-prescription medications, vitamins, licorice (in large amounts) or dietary supplements within 7 days of administration of the study drug. Excluded from this list is intermittent use of acetaminophen at doses of \</=2 g/day. Herbal supplements must be discontinued 7 days prior to the initial dose of study drug.
• Consumption of more than 300 mg of caffeine per day (\>3 cups of coffee or 6-12 ounces of soda) within 7 days prior to dosing.
• Presence of any acute illness within 7 days of Day -1 in any Study Period.
• Breastfeeding or a positive serum pregnancy test at the Screening Visit or on Day -1 in any Study Period

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Quintiles Phase I Services - Overland Park

Overland Park, Kansas, 66211-1553, United States

Location

MeSH Terms

Conditions

Pseudomonas Infections

Interventions

Fosfomycin

Condition Hierarchy (Ancestors)

Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2014
• First Posted: June 30, 2014
• Study Start: August 1, 2014
• Primary Completion: October 1, 2014
• Study Completion: October 1, 2014
• Last Updated: April 4, 2016

Record last verified: 2015-01

Locations

US (1)