Single-Dose ZTI-01 for Pediatric Patients

(Pediatric_PK Trial)

Recruiting at 4 trial locations

Overseen By Steve Gelone

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Nabriva Therapeutics AG

Must be taking: Antibiotics

Must not be taking: Anticonvulsants, QT-prolonging drugs

Disqualifiers: HIV, Hepatitis B/C, Seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

21 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must be receiving standard antibiotics for a bacterial infection to participate.

Is ZTI-01 (fosfomycin for injection) safe for use in humans?

ZTI-01 (fosfomycin for injection) has been used in many countries outside the USA since the 1970s for treating various infections, suggesting a history of use in humans. However, specific safety data for pediatric patients or for conditions other than complicated urinary tract infections and acute pyelonephritis is not detailed in the provided research articles. ^{1 2 3 4 5}

How is the drug ZTI-01 different from other treatments for pediatric patients?

ZTI-01, or fosfomycin for injection, is unique because it is administered as a single-dose intravenous treatment, which can be more convenient and potentially improve adherence compared to multi-dose regimens. This is particularly beneficial for pediatric patients who may have difficulty with frequent dosing. ^{6 7 8 9 10}

What is the purpose of this trial?

Phase 1 study, a single dose of ZTI-01 given to pediatric subjects (under 12 years of age) who require antibiotic therapy to see what the body does to the drug (pharmacokinetics) and to compare if these effects are similar to those observed in adults at a 6g ZTI-01 dose. Study will help establish pediatric dosing in younger children by age cohort. This is a multiple-center, open-label, PK study of ZTI-01 (fosfomycin for injection) single dose scaled by allometric weight-modeling from an adult ZTI-01 dose of 6 grams. Eligible subjects must be receiving standard of care antibiotics for proven or suspected bacterial infection or for peri-operative prophylaxis surgery (in or out of hospital).

Research Team

John S Bradley, MD

Principal Investigator

Rady Children's Hospital / Department of Pediatrics, University of California, School of Medicine

Jennifer Schranz, MD

Principal Investigator

Nabriva Therapeutics

Eligibility Criteria

This trial is for children under 12 years old who are hospitalized and currently receiving antibiotics for a bacterial infection or as prevention around surgery. They must have normal organ function, not be at risk of pregnancy, and have proper intravascular access. Children with seizure disorders, significant lab abnormalities, known drug allergies, impaired kidney function, or certain viral infections cannot participate.

Inclusion Criteria

Has sufficient intravascular access to receive study drug through peripheral or central line

Signed consent/assent

If of reproductive potential, agrees to avoid becoming pregnant or impregnating a partner from the time of consent through 24 hours after completion of study drug administration

Exclusion Criteria

I have not been in this trial or taken ZTI-01 or fosfomycin in the last 30 days.

I have surgery planned during the time my blood will be tested for fosfomycin levels.

Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) of administration of the study drug

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single, weight-adjusted dose of ZTI-01 via continuous IV infusion or syringe pump over a 1-hour period

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and pharmacokinetics, including blood collection for fosfomycin concentration measurement and assessment of adverse events

1 day

1 visit (in-person)

Treatment Details

Interventions

• ZTI-01

Trial Overview The study tests how a single dose of ZTI-01 (an antibiotic) behaves in the bodies of children compared to adults. It's an open-label Phase 1 trial across multiple centers aiming to find the right pediatric dosage by scaling from an adult dose using weight-based calculations.

Participant Groups

Group I: ZTI-01 Cohort 3c ≥ 6 to < 24 mos of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group II: ZTI-01 Cohort 3b ≥ 3 to < 6 mos of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group III: ZTI-01 Cohort 3a Birth to < 3 mos of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 75 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group IV: ZTI-01 Cohort 2 ≥ 2 to <6 years of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group V: ZTI-01 Cohort 1 ≥ 6 to <12 years of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

ZTI-01 is already approved in United States for the following indications:

Approved in United States as ZTI-01 for:

• Complicated urinary tract infections (cUTI)
• Acute pyelonephritis (AP)

Who Is Running the Clinical Trial?

Nabriva Therapeutics AG

Lead Sponsor

Trials

10

Recruited

2,100+

Findings from Research

Fosfomycin for injection demonstrated physical compatibility with 77% of the 95 intravenous drugs tested, indicating it can be safely co-administered with many other medications in clinical settings.

However, 22 drugs were found to be incompatible with fosfomycin in at least one of the two diluents tested (0.9% sodium chloride and 5% dextrose), highlighting the need for careful consideration when combining treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical compatibility of fosfomycin for injection with select i.v. drugs during simulated Y-site administration. Monogue, ML., Almarzoky Abuhussain, SS., Kuti, JL., et al.[2019]

Fosfomycin, a bactericidal antibiotic that has been used since the 1970s, is being developed for intravenous use in the USA to combat drug-resistant bacteria, particularly for complicated urinary tract infections and acute pyelonephritis.

The review highlights the importance of introducing intravenous fosfomycin (ZTI-01) in the US market as a necessary option to address the growing challenge of antibiotic resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZTI-01 (fosfomycin for injection) in the treatment of hospitalized patients with complicated urinary tract infections. Burgos, RM., Rodvold, KA.[2019]

Fosfomycin (ZTI-01) shows effective activity against drug-resistant bacteria, including ESBL-producing and carbapenem-resistant strains, in a murine thigh infection model, indicating its potential for treating serious infections.

The study identified that the pharmacokinetic/pharmacodynamic (PK/PD) index, specifically the AUC/MIC ratio, is crucial for determining the efficacy of fosfomycin, with optimal ratios linked to both bacterial stasis and survival in infected mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Lepak, AJ., Zhao, M., VanScoy, B., et al.[2020]

Fosfomycin, particularly in its intravenous form ZTI-01, shows promise for treating infections caused by multidrug-resistant bacteria, with a focus on understanding its pharmacokinetic-pharmacodynamic (PK-PD) properties for effective dosing.

The study identified a critical PK-PD index that correlates with fosfomycin's efficacy against resistant E. coli, suggesting specific dosing regimens are necessary to achieve desired bacterial stasis and reductions in bacterial counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model. VanScoy, BD., McCauley, J., Ellis-Grosse, EJ., et al.[2018]

In a study involving 465 hospitalized adults with complicated urinary tract infections (cUTI) or acute pyelonephritis (AP), ZTI-01 (fosfomycin) demonstrated noninferiority to piperacillin-tazobactam, achieving a success rate of 64.7% compared to 54.5% for the comparator, indicating its effectiveness against serious Gram-negative infections.

ZTI-01 was well tolerated, with most side effects being mild and temporary, suggesting it is a safe treatment option for patients with cUTI and AP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial. Kaye, KS., Rice, LB., Dane, AL., et al.[2020]

Isavuconazole, given as isavuconazonium sulfate, was found to be safe and well-tolerated in a phase 1 study involving 46 immunocompromised pediatric patients, with no significant safety concerns related to age, sex, race, or body mass index.

The pharmacokinetics of isavuconazole in pediatric patients showed that over 80% of those receiving intravenous and over 76% receiving oral doses achieved plasma drug levels within the target range established for adults, indicating effective dosing for treating invasive fungal infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients. Arrieta, AC., Neely, M., Day, JC., et al.[2022]

Invasive fungal infections (IFIs) are a significant health risk for immunocompromised children, highlighting the need for effective prevention and treatment strategies.

Current antifungal treatments for pediatric patients are limited due to a lack of approved agents, established dosages for different age groups, and insufficient postmarketing safety and efficacy data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of antifungals in pediatric patients. Groll, AH.[2019]

There has been limited progress in treating invasive fungal infections over the past 40 years, but recent advancements have improved our understanding of the safety and pharmacokinetics of antifungal agents, particularly in children.

Most pediatric antifungal treatment strategies are currently based on adult data due to a lack of studies in children, but ongoing research aims to develop specific dosing strategies that will better serve pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mycoses in pediatric patients. Steinbach, WJ., Walsh, TJ.[2006]

Pediatric patients have different pharmacokinetic parameters compared to adults, which means they need individualized medication dosing rather than just smaller doses of adult medications.

The lack of specific dosing guidelines and appropriate pediatric dosage forms can lead to serious dosing errors and complications, highlighting the need for tailored dosing strategies to ensure safety and efficacy in young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosing considerations in the pediatric patient. Skaer, TL.[2013]

There is limited information on the pharmacokinetics and pharmacodynamics of antifungal drugs in children, leading to a reliance on adult studies for dosing and efficacy, despite the increasing reports of safety and potential effectiveness in pediatric patients.

Future research is essential to determine the optimal dosing of antifungal agents for children to ensure effective prevention of invasive fungal disease while minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antifungal prophylaxis in pediatric patients undergoing therapy for cancer: drugs and dosing. Lehrnbecher, T.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Physical compatibility of fosfomycin for injection with select i.v. drugs during simulated Y-site administration. [2019]

2. England pubmed.ncbi.nlm.nih.gov

ZTI-01 (fosfomycin for injection) in the treatment of hospitalized patients with complicated urinary tract infections. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients. [2022]

7. Ireland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of antifungals in pediatric patients. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Mycoses in pediatric patients. [2006]

9. United States pubmed.ncbi.nlm.nih.gov

Dosing considerations in the pediatric patient. [2013]

10. United States pubmed.ncbi.nlm.nih.gov

Antifungal prophylaxis in pediatric patients undergoing therapy for cancer: drugs and dosing. [2015]