Study of Potential for Interaction of Fluconazole With F901318
Condition: Invasive Aspergillosis
MeSH terms: Aspergillosis
Study type: Interventional
Phase: Phase 1

Summary: 
      This will be an open label study in two parts. In the first part, F901318 (dose 2 mg/kg IV
      over 4 hours, Day 1) will be followed by F901318 (2 mg/kg IV over 4 hours) given on Day 8,
      after dosing with fluconazole 800 mg daily for 1 day (Day 4) and 400 mg daily orally for 4
      days (Days 5 to 8). Up to twenty subjects will be included in two cohorts which will undergo
      the same dosing schedules of fluconazole and F901318 and undergo the same procedures. The
      first cohort will consist of 12 subjects studied in two groups of six subjects each. If there
      is clearly a difference in F901318 kinetics detectable before and after dosing with
      fluconazole in this first cohort, the second cohort will not be studied. If there is no clear
      difference, the second cohort will also be studied to give a final result. In this cohort,
      based on the pharmacokinetic findings in cohort 1, the dose of F901318 may be increased to up
      to 4 mg/kg to establish a dose suitable for phase 2 evaluation. PK sampling for plasma
      F901318 will continue from before the first dose up to and including 72 hours after dosing.
      PK sampling for fluconazole will continue from before the first dose and up to 72 hours after
      the fifth dose. A follow up visit will be conducted 7 +/- 2 days after discharge from the
      clinical unit following completion of blood sampling following the second dose of F901318 and
      the fifth dose of fluconazole.

      The second part of the study will take place if no appreciable change in the pharmacokinetics
      of either F901318 or fluconazole has been observed in either the first or the second cohorts
      in the first part of the study. This second part will enrol 12 subjects. These subjects will
      receive fluconazole 800 mg daily for one day (Day 1) and 400 mg daily orally for 4 days (Days
      2 to 5) in combination with F901318 which will be given in a dose of up to 4 mg/kg IV bid for
      one day (Day 1) followed by 7 doses of intravenous F901318 up to 2.5 mg/kg bid (Days 2 to 5).
      Pharmacokinetic profiles of F901318 and fluconazole will be obtained during dosing and over a
      72-hour period following the final dose of both compounds.
    

Detailed description: 
      Part 1

      Treatment Period (Day -1 to Day 11; visit 2):

      Subjects will be admitted to the clinical unit in the afternoon of Day -1 and will remain on
      site until completion of the 72-hour post fluconazole and F901318 dose study-related
      procedures on Day 11. Admission procedures (Day -1) include a review of inclusion/exclusion
      criteria, weight, vital signs, test for drugs of abuse, alcohol and smoking and pregnancy
      where appropriate (must be negative), and a review of concomitant medication and adverse
      events. Blood (haematology, clinical chemistry and coagulation function) and urine
      (urinalysis) will be obtained for safety evaluations. Breakfast will be taken 30-60 minutes
      prior to dosing)

      Days 1 - 4: F901318 (2 mg/kg IV for cohort 1 and up to 4 mg/kg IV for cohort 2) over 4 hours
      will be administered on Day 1. Blood samples for determination of plasma levels of F901318
      will be collected predose and at the following time points up to 72 hours post-dose:

      1, 2, 3, 4, 4.25, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 38, 48, 72 hours

      Blood pressure, and pulse (lying and standing), and core temperature will be recorded at the
      following times on Day 1:

      Prior to dosing, 1, 2, 4, 6, 8, 12 and 24 hours following dosing.

      Twelve lead ECGs will be recorded prior to dosing and 1, 4, 8, 12 and 24 hours after dosing
      with F901318.

      Telemetry will be set up 1 hour prior to dosing with F901318 and will continue for 12 hours
      thereafter. It may be extended to 24 hours at the discretion of the investigator.

      Day 4 to Day 7: After an overnight fast from midnight, fluconazole will be administered in a
      dose of 800 mg on day 4 and 400 mg daily on Days 5-7 in the morning.

      On Day 4, pharmacokinetic blood samples will be drawn for fluconazole estimation at the
      following times in relation to dosing:

      -5 minutes, 15, 30, 45, 60, 75, 90, 120 min. 3, 4, 6, 8, 10, 12, 16, 20 hours.

      Blood samples for determination of peak (4 hours) and trough (predose) plasma levels of
      fluconazole will be collected on Days 5 to 7 inclusive. Dosing on these days will be before
      breakfast is taken.

      Vital signs (supine and standing pulse rate and blood pressure and oral temperature) will be
      recorded prior to dosing on Day 4 and at the following times thereafter:

      1, 4, 8, 12, 24, 48 hours

      12 lead ECGs will be recorded prior to dosing on Day 4 and at the following times thereafter:

      24, 48 hours.

      Fasting blood samples will be obtained for haematology, coagulation and clinical chemistry
      prior to dosing with fluconazole on Day 4 and at the following time points:

      48 hours

      A spot urine sample will be obtained for urinalysis prior to dosing with fluconazole on Day 4
      and at the following time points:

      48 hours

      Days 8-11: Subjects will fast for 12 hours before dosing on Day 8. Water will be allowed ad
      libitum. Blood samples for determination of baseline plasma levels of fluconazole and F901318
      blank and safety laboratory analyses (clinical chemistry, haematology and coagulation
      function) will be collected pre-dose on Day 8. F901318 (2 mg/kg IV for cohort 1 and up to 4
      mg/kg IV for cohort 2) will be administered intravenously over 4 hours in the morning.
      Fluconazole will be administered orally on Day 8 at the same time as the start of the
      infusion. Blood samples for determination of plasma levels of fluconazole will be collected
      at the following time points after the dose of fluconazole:

      15, 30, 45, 60, 75, 90 min, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 72 hours.

      Blood samples for plasma concentrations of F901318 will be collected at the following times
      after the start of the infusion (assuming an infusion duration of 4 hours).

      1, 2, 3, 4, 4.25, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 38, 48, 72 hours

      Blood pressure, and pulse (lying and standing) and core temperature will be recorded at the
      following times on Day 8:

        1. 2, 4, 6, 8, 12 and 24, 48, 72 hours following the start of dosing with F901318.

           Twelve lead ECGs will be recorded at 1, 4, 8, 12, 24, 48, 72 hours after dosing with
           F901318.

           Telemetry will be commenced 1 hour prior to dosing with F901318 and will continue for 12
           hours thereafter. This monitoring may be extended to 24 hours at the discretion of the
           Principal Investigator.

           Adverse events and concomitant medications will be recorded throughout.

           Subjects will be discharged after all 72 hours measurements and observations have been
           completed, so long as they are fit to leave in the opinion of the Investigator.

           Post Study Visit: (visit 3) After discharge on Day 11, all subjects will return to the
           study centre on days 16-20 to complete a post study follow-up visit.

           Total blood loss for each subject in this part of the study will be 202 mL
           approximately.

           Part 2

           Treatment Period (Day -1 to Day 8; visit 3):

           Subjects will be admitted to the clinical unit in the afternoon of Day -1 and will
           remain on site until completion of the 72-hour post fluconazole and F901318 dose
           study-related procedures on Day 8. Admission procedures (Day -1) include a review of
           inclusion/exclusion criteria, weight, vital signs, test for drugs of abuse, alcohol and
           smoking and pregnancy where appropriate (must be negative) and a review of concomitant
           medication and adverse events. Blood (haematology, clinical chemistry and coagulation
           function) and urine (urinalysis) will be obtained for safety evaluations. Subjects will
           fast from midnight.

           Day 1: F901318 up to 4 mg/kg IV over 4 hours bid will be administered starting at time 0
           and fluconazole 800 mg orally at time 0. A second dose of F901318 (up to 4 mg/kg IV over
           4 hours) will be given starting at 12 hours post the morning dose. Water will be allowed
           ad libitum. Blood samples for determination of plasma levels of F901318 will be
           collected predose and at the following time points:

        2. 4, 4.25, 4.5, 5, 6, 8, 10, 12 (just before second infusion), 16 (5 minutes before end of
           infusion) hours.

      Pharmacokinetic blood samples will be drawn for fluconazole estimation pre-dose at the
      following times after dosing:

      15, 30, 45, 60, 75, 90, 120 min. 3, 4, 6, 8, 10, 12, 16, 20 hours.

      Blood pressure, and pulse (lying and standing), and oral temperature will be recorded at the
      following times on Day 1:

      Prior to dosing, 1, 2, 4, 6, 8 and 12 hours following dosing.

      Twelve lead ECGs will be recorded prior to dosing and 1, 4, 8, and 12 hours after dosing.

      Telemetry will be set up 1 hour prior to dosing with F901318 and will continue for 12 hours
      thereafter. This monitoring may be extended to 24 hours at the discretion of the Principal
      Investigator.

      Local tolerability will be determined prior to dosing with F901318 and at the end of each
      infusion.

      Day 2 to Day 8: F901318 will be administered intravenously twice daily (7 doses of up to 2.5
      mg/kg each infused over 4 hours) (Days 2 to 5).

      Fluconazole will be administered after fasting from 12 midnight in a dose of 400 mg daily in
      the morning for 4 doses (Days 2 to 5).

      Blood samples for determination of peak (4 hours) and trough (predose) plasma levels of
      fluconazole and F901318 (prior to start of infusion and 5 minutes before end of infusion)
      will be collected on Days 2 to 4 inclusive.

      Vital signs (supine and standing pulse rate and blood pressure, core temperature and local
      tolerability) will be recorded prior to and at the end of each infusion on Days 2, 3 and 4

      12 lead ECGs will be recorded prior to morning dosing on Days 2, 3, 4 and 5

      Fasting blood samples will be obtained for haematology, coagulation and clinical chemistry
      prior to dosing with fluconazole on Days 2, 5 and on Day 8 (72 hours after the last doses of
      F901318 and fluconazole).

      A spot urine sample will be obtained for urinalysis prior to dosing with fluconazole on Days
      2, 5 and on Day 8 (72 hours after the last doses of F901318 and fluconazole).

      On Day 5, pharmacokinetic blood samples will be drawn for F901318 estimation at the following
      times in relation to dosing:

      -5 minutes, 2, 4, 4.25, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 36, 48, 72 hours.

      On Day 5, pharmacokinetic blood samples will be drawn for fluconazole estimation at the
      following times in relation to dosing:

      -5 minutes, 15, 30, 45, 60, 75, 90, 120 min. 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 72
      hours.

      Vital signs and local tolerability will be obtained prior to dosing on Day 5 and at the end
      of the F901318 infusion.

      Telemetry will be set up 1 hour prior to dosing with F901318 on Day 5 and will continue for
      12 hours thereafter. This monitoring may be extended to 24 hours at the discretion of the
      Principal Investigator.

      Day 8: An ophthalmology assessment will be performed. Subjects will be discharged from the
      Unit following collection of the final assessments and blood samples and completion of the
      ophthalmology assessment.

      Adverse events and concomitant medications will be recorded throughout.

      Post Study Visit (visit 4):

      After discharge on Day 8, all subjects will return to the study centre on days 13-17 to
      complete a post study follow-up visit.

      Total blood loss for each subject in this part of the study will be 224 mL approximately.
    

Intervention name(s): F901318; Fluconazole
Intervention type(s): Drug; Drug
Intervention description(s): Administration of F901318 intravenously; Oral administration
Other intervention name(s): Antifungal agent; Antifungal agent
Intervention MeSH terms: Fluconazole; Antifungal Agents; Clotrimazole; Miconazole; Olorofim
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment