Penetration of the Innovative Antibiotic Gepotidacin Into Prostate and Tonsillar Tissue (AB-Direct)

Institut National de la Santé Et de la Recherche Médicale, France

Status and phase

Completed

Phase 1

Conditions

Gonorrhea

Infection, Bacterial

Treatments

Drug: Gepotidacin

Study type

Interventional

Funder types

Other

Identifiers

NCT04484740

2019-004308-37 (EudraCT Number)

C19-28

Details and patient eligibility

About

Gepotidacin is a new antibiotic that may potentially be used to treat prostatic infections and pharyngeal gonorrhoea. To date, no data exists on gepotidacin pharmacokinetics in those tissues. The present study is being carried out to determine concentrations of gepotidacin in plasma, prostate and tonsillar tissue of patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostate hyperplasia (BPH) or tonsillectomy (TE). This will contribute to a more complete understanding of the drug's penetration to its site of action.

Full description

A single dose of 1500 mg gepotidacin will be administered to patients who will undergo radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE). The individual time-points of gepotidacin administration will be chosen to ensure that the time-point of tissue removal corresponds with one of six different sampling time-points, as closely as possible.

After study drug administration RPE or TE will be performed according to clinical routine.

Subsequently, microdialysis (MD) probes will be inserted in the removed tissue (tonsillar or prostate tissue) ex-vivo and MD will be performed to determine unbound drug concentrations in the tissue.

Plasma PK samples will be collected just before study drug administration and up to 48h after administration of gepotidacin.

Since MD provides the concentration of the unbound fraction of gepotidacin, for comparison we will calculate the unbound fraction of the concentration values obtained through blood sampling. To this end, we will determine the protein binding using ultrafiltration for each subject at the time-point closest to the Cmax. The individual protein binding can then be used to calculate the unbound plasma fraction of gepotidacin. This will allow to transform the plasma PK data to the same scale as the microdialysis data.

Samples will be analysed using non-compartmental analysis (NCA) for plasma concentrations and population pharmacokinetic models (PopPK) for tissue concentrations pooled with plasma concentrations.

Enrollment

53 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Cohort A only:

Clinically localized prostate cancer or benign prostate hyperplasia
Male patient scheduled for prostatectomy

Cohort B only:

Male or female patient scheduled for complete tonsillectomy
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP) or
- Is a WOCBP with a highly sensitive negative pregnancy test

Both Cohorts:

Age: above 18 years
Body weight ≥40 kg and body mass index (BMI) within the range 18.5 - 32.0 kg/m2
A signed and dated written informed consent form
The subject is able to understand and willing to comply with protocol requirements and timetables, instructions and protocol-stated restrictions
Negative serology (human immunodeficiency virus, hepatitis B-AG and C-AB) at screening
Patient with a social security or health insurance (if applicable according to the local regulation)

Exclusion criteria

Cohort A only:

• Any concerns of the investigator or the treating urologists that the participation in the study might impair histological assessment of the prostate tissue such as (but not limited to): lack of representative histology via previous biopsy AND inability to safely insert microdialysis probes in tissue with sufficient distance to the tumor (e.g. large or diffuse tumor, lack of MRI or PET image to locate tumor within the organ).

Cohort B only:

Pregnancy
Women of childbearing potential who are not employing adequate contraceptive measures
Accepted contraceptive measures are (have to be employed for at least 30 days prior to dosing until one week after the final examination):
- intrauterine device
- intrauterine hormone-releasing system
- implantable progestogen-only hormone contraception associated with inhibition of ovulation
- combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable)
- progestogen-only hormone contraception associated with inhibition of ovulation (oral, injectable)
- condoms
- sexual abstinence
- surgical sterilization
Acute tonsillitis or peritonsillar abscess
History of peritonsillar abscess
Tonsillectomy for cervical lymph node metastasis of cancer of unknown primary

Both Cohorts:

• Individuals deprived of liberty and protected persons (under guardianship or curatorship).

Medical Conditions

Clinically significant abnormality in the past medical history or at the Screening physical examination that in the investigator's opinion may place the participant at risk or interfere with outcome variables of the study. This includes, but is not limited to, history or current cardiac, hepatic, renal, neurologic, gastrointestinal (GI), respiratory, hematologic, or immunologic disease.
Any surgical or medical condition that may be aggravated by inhibition of acetylcholinesterase, such as:
- Poorly controlled asthma or chronic obstructive pulmonary disease at baseline and, in the opinion of the investigator, not stable on current therapy
- Acute severe pain, uncontrolled with conventional medical management
- Active peptic ulcer disease
- Parkinson disease
- Myasthenia gravis
- A history of seizure disorder requiring medications for control (this does not include a history of childhood febrile seizures)
Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study intervention, or any other condition that may place the participant at risk, in the opinion of the investigator.
Within 2 months before Screening, either a confirmed history of Clostridium difficile diarrhoea infection or a past positive C. difficile toxin test.
Uncompensated heart failure
Severe left ventricular hypertrophy
History of significant vasovagal and/or syncopal episodes or episodes of symptomatic bradycardia
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
History of drug and/or alcohol abuse within 6 months before screening, as determined by the investigator
History of sensitivity to any of the study drug, components thereof, or a history of drug or other allergy that, in the opinion of the investigator contraindicates their participation.
Subject is taking QT-prolonging drugs or drugs known to increase the risk of torsades de points (TdP) per the www.crediblemeds.org "Known Risk of TdP" category at the time of screening that cannot be discontinued. If discontinued they should be discontinued at screening and can be resumed after the last PK sample.
Subject is taking strong cytochrome P450 enzyme 3A4 (CYP3A4) inhibitors CYP3A4 that cannot be discontinued. If discontinued, they should be discontinued at a minimum of 12 hours or 5 half-lifes from the scheduled gepotidacin dose and can be resumed after the last PK sample.
Subject is taking strong P glycoprotein (P-gp) inhibitors that cannot be discontinued. If discontinued, they should be discontinued at a minimum of 12 hours or 5 half-lifes from the scheduled gepotidacin dose and can be resumed after the last PK sample.

Prior/Concurrent Clinical Study Experience

• Previous exposure to gepotidacin. Participant has participated in a clinical trial and has received an investigational product prior to gepotidacin administration within 30 days, 5 half-lives, or twice the duration of the biological effect of investigational product (whichever is longer) Non-interventional studies are excepted.

Diagnostic assessments

Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN).
Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
History of any kidney disease or current or chronic history of impaired renal function as indicated by an estimated creatinine clearance <60 mL/min.
History of regular alcohol consumption within 6 months of screening defined as an average weekly intake of >21 units (or an average daily intake of >3 units) for males or an average weekly intake of >14 units (or an average daily intake >2 units) for females. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of spirits, or 100 mL of wine.
History of regular use of more than 10 cigarettes or equivalent per day.
Clinically significant abnormal findings in serum chemistry, hematology, or urinalysis results obtained at screening at investigators discretion
Baseline corrected QT interval using the Fridericia formula (QTcF) of >450 msec.

Other Exclusions

Participant has donated blood in excess of 500 mL within 12 weeks prior to dosing or participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
Participant is unable to comply with all study procedures, in the opinion of the investigator.
Participant should not participate in the study, in the opinion of the investigator or sponsor.