Study of Potential for Interaction of Fluconazole With F901318
Study of Potential for Interaction of Fluconazole With F901318
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.
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.
Inclusion Criteria:

 1. Subjects will be males and females of any ethnic origin aged between 18 and 45 years
 of age and weighing 50-100 kg inclusive.

 2. Subjects must be in good health, as determined by a medical history, physical
 examination, 12-lead electrocardiogram (ECG) and clinical laboratory evaluations
 (congenital non haemolytic hyperbilirubinaemia is acceptable).

 3. Subjects will have given their written informed consent to participate in the study
 and to abide by the study restrictions.

 Exclusion Criteria:

 1. Male and female subjects who are not willing to use appropriate contraception during
 the study and for three months thereafter.

 2. Subjects who have received any prescribed systemic or topical medication within 14
 days of the dose administration unless in the opinion of the Investigator and the
 Medical Monitor the medication will not interfere with the study procedures or
 compromise safety.

 3. Subjects who have used any non-prescribed systemic or topical medication (including
 herbal remedies) within 7 days of the dose administration (with the exception of
 vitamin/mineral supplements and paracetamol) unless in the opinion of the Investigator
 and the Medical Monitor the medication will not interfere with the study procedures or
 compromise safety.

 4. Subjects who have received any medications, including St John's Wort, known to
 chronically alter drug absorption or elimination processes within 30 days of the dose
 administration unless in the opinion of the Investigator and the Medical Monitor the
 medication will not interfere with the study procedures or compromise safety. For at
 least 2 weeks prior to dosing and until all blood samples and observations are
 completed on Day 18 +/- 2 (Part 1) or Day 15 +/- 2 (Part 2), subjects will not be
 allowed to eat any food or drink any beverage containing alcohol, grapefruit or
 grapefruit juice, apple or orange juice, vegetables from the mustard green family e.g.
 kale, broccoli, watercress, spring greens, kohlrabi, Brussels sprouts, mustard and
 charbroiled meats.