Mass Balance Recovery, Metabolite Profile, and Metabolite Identification of [14C]-Paxalisib in Healthy Male Subjects

Inclusion criteria

• Healthy males.
• Aged 30 to 65 years inclusive at the time of signing informed consent.
• Body mass index (BMI) of 18.0 to 35.0 kg/m2 as measured at screening.
• Must be willing and able to communicate and participate in the whole study.
• Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per day).
• Must provide written informed consent.
• Must agree to adhere to the contraception requirements defined in study protocol.

Exclusion criteria

• Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1.
• Subjects who are, or are immediate family members of, a study site or sponsor employee.
• Evidence of current SARS-CoV-2 infection.
• History of any drug or alcohol abuse in the past 2 years.
• Regular alcohol consumption >21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type).
• A confirmed positive alcohol breath test at screening or admission.
• Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission.
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
• Subjects with pregnant or lactating partners.
• Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study.
• Subjects who have been administered IMP in an ADME study in the last 12 months.
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
• Clinically significant abnormal clinical chemistry, haematology, or urinalysis as judged by the investigator (laboratory parameters are listed in study protocol).
• Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in study protocol)
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV) antibody results
• Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation.
• History of clinically significant cardiovascular, renal, hepatic, chronic respiratory disease, neurological, or psychiatric disorder, as judged by the investigator.
• History of clinically significant GI disease, especially peptic ulceration, GI bleeding, ulcerative colitis, Crohn's Disease, or Irritable Bowel Syndrome.
• Any history of pre-diabetes, diabetes mellitus (any type), or hyperglycaemia. At screening, fasting blood glucose and HbA1c must be within the normal range.
• History or presence of significant dermatological disorders or skin rashes, as judged by the investigator.
• Subject had a QTcF of >450 msec based on ECG at screening or at pre dose, or a history of additional risk factors for Torsades de Pointe (e.g., hypokalaemia, hypomagnesia, a family history of long QT syndrome).
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
• Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
• Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood.
• Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 4 g of paracetamol per day) within 14 days before IMP administration (see Section 11.4). COVID-19 vaccines are accepted concomitant medications, except for within 72 h of dosing. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator.
• Subjects who have had a COVID-19 vaccine within 72 h (3 days) before IMP administration.
• History of GI surgery (with the exception of appendectomy unless it was performed within the previous 12 months).
• Acute diarrhoea or constipation in the 7 days before the predicted Day 1. If screening occurs >7 days before the Day 1, this criterion will be determined on Day 1. Diarrhoea will be defined as the passage of liquid faeces and/or a stool frequency of greater than 3 times per day. Constipation will be defined as a failure to open the bowels more frequently than every other day.
• Failure to satisfy the investigator of fitness to participate for any other reason.