A Single Centre, Open-label, 2-period Fixed-sequence, Phase I Clinical Study to Evaluate the Effect of BV100 on the Pharmacokinetics of Polymyxin B in Healthy Volunteers

BV100-011 A Single Centre, Open-label, 2-period Fixed-sequence, Phase I Clinical Study to Evaluate the Effect of BV100 on the Pharmacokinetics of Polymyxin B in Healthy Volunteers

This is an open-label, fixed sequence Phase I clinical study to evaluate the effect of multiple doses of BV100 on the PK of polymyxin B in healthy participants (HPs).

This is an open-label, fixed sequence Phase I clinical study to evaluate the effect of multiple doses of BV100 on the PK of polymyxin B in healthy participants (HPs).

BV100 (rifabutin for infusion) is being developed as an IV formulation for the treatment of serious infections due to Acinetobacter baumannii, including nosocomial pneumonia and blood stream infection (BSI).

Polymyxin B for Injection (Polymyxin B sulfate) is a polypeptide antibiotic that is derived from Bacillus polymyxa (more recently termed Paenibacillus polymyxa). Polymyxin B sulfate is an antibiotic often used to treat serious infections due to aerobic Gram-negative pathogens in patients with limited treatment options.

BV100 has shown strong synergy with polymyxin B against carbapenem-resistant A. baumannii (CRAB).

Study participants will be divided into two sequential groups, each consisting of 8 (eight) participants:

• Group 1 will receive all doses of polymyxin B (Period 1), BV100 (Period 2), and the combination of BV100 and polymyxin B (Period 2) diluted in 500 mL sterile 0.9% saline per infusion; and,
• Group 2 will receive all doses of polymyxin B (Period 1), BV100 (Period 2), and the combination of BV100 and polymyxin B (Period 2) diluted in 250 mL sterile 0.9% saline per infusion.

Each subject will receive a single 50 mg IV dose of polymyxin B on Period 1 Day 1.

BV100 will be administered as a 300 mg IV infusion every 12 hours in Period 2 from Day 1 to Day 3, totalling 6 doses.

On Period 2 Day 4, 300 mg IV dose of BV100 will be co-administered with a 50 mg IV dose of polymyxin B in the same infusion bag.

Main Inclusion Criteria:

1. Participants who were able to understand and follow instructions during the study.

2. Participants who signed informed consent.

3. Male participants ≥ 18 and ≤ 55 years of age; female participants ≥ 18 and ≤ 55 years of age of non-childbearing potential and non-lactating, with absence of childbearing potential defined as follows:

   1. Female participants 50 years of age or older, in menopause for 24 consecutive months and not receiving any hormone replacement therapy within 24 months prior to inclusion into the study
   2. Female participants who underwent surgical sterilization
   3. Female participants who underwent hysterectomy
   4. Female participants with documented premature ovarian failure

4. Weight within a BMI range of 19.0 - 30.0 kg/m2.

5. Estimated glomerular filtration rate (eGFR) according to the MDRD formula : > 60 mL/min/1.73 m2.

Main Exclusion Criteria:

1. Unwilling or unable to give informed consent.
2. As a result of the medical screening process, the study physician considered the participant unfit for the study.
3. Male participants with female partners who are lactating or pregnant.
4. Known or suspected history of hypersensitivity to rifabutin or to drugs of a similar chemical class including rifampicin, rifapentine, rifaximin.
5. Known or suspected history of hypersensitivity to polymyxin B or colistin.
6. History of allergic reactions leading to hospitalization or any other allergic conditions (including drug allergies, asthma, eczema, anaphylactic reactions but excluding untreated, asymptomatic, seasonal allergies) which the Investigator considers may affect the safety of the participant and/or outcome of the study.
7. History of antibiotic associated diarrhoea within the last year.
8. Participants with ECG abnormalities (history, or evidence of second-degree heart block of Mobitz type II, third degree heart block, or any abnormality considered relevant by the Investigator), QTcF > 450 ms, PR > 210 ms, or QRS duration > 110 ms.
9. Supine systolic blood pressure > 150 mmHg or < 95 mmHg or diastolic blood pressure > 95 mmHg or < 45 mmHg at Screening or Period 1 Day 1 prior to dosing (any clinically relevant abnormal blood pressure results may be repeated once and if the repeat result is within the normal range, it is not considered to have met the exclusion criterion). Pulse rate > 110 or < 40 beats per minute at Screening or Period 1 Day 1 prior to dosing.
10. Clinically relevant abnormal values for leukocytes (total WBC), neutrophils, and lymphocytes (total), above the upper level of normal (ULN) or below the lower limit of normal (LLN) at screening, at the Investigator's discretion. Any clinically relevant abnormal value of these parameters may be repeated during screening.
11. Clinically relevant abnormal values for Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and creatinine, above the ULN at Screening, at the Investigator's discretion. Any clinically relevant abnormal value of these parameters may be repeated during screening.
12. Screening laboratory test values other than AST, ALT, ALP, creatinine, leucocytes, lymphocytes or neutrophils for haematology, biochemistry, or urinalysis must not exceed the reference range. Minor deviations from normal are allowed, if they are not considered clinically significant by the Investigator.