Mass Balance Recovery, Metabolite Profile, and Metabolite Identification of [14C]-Paxalisib in Healthy Male Subjects
Study Details
Study Description
Brief Summary
Single-centre, open-label, non-randomised study to assess the mass balance recovery, PK, metabolite profile, and metabolite identification of a single oral dose of 14C labelled paxalisib ([14C] Paxalisib) in healthy male subjects.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: [14C]-Paxalisib Capsule Subjects will be dosed on the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects will remain resident in the clinical unit until 168 h post dose (Day 8) and this may be extended up to a maximum of 48 h (i.e., up to Day 10). |
Drug: [14C]-Paxalisib Capsule
Each subject will receive a single dose 15 mg (NMT 3.5 MBq), administered orally in the fasted state with with 240 mL water.
Other Names:
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Outcome Measures
Primary Outcome Measures
- To determine the mass balance recovery after a single oral dose of carbon-14 ([14C])-Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Mass balance recovery of total radioactivity (TR) in all excreta (urine and faeces): CumAe (amount excreted) and Cum%Ae
- To provide plasma samples for metabolite profiling and structural identification [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Collection of plasma samples for metabolite profiling, structural identification, and quantification analysis of paxalisib metabolites
- To provide urine samples for metabolite profiling and structural identification [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Collection of urine samples for metabolite profiling, structural identification, and quantification analysis of paxalisib metabolites
- To provide faecal samples for metabolite profiling and structural identification [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Collection of faecal samples for metabolite profiling, structural identification, and quantification analysis of paxalisib metabolites
Secondary Outcome Measures
- To determine the routes and rates of elimination of [14C]-Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Calculation of Ae, %Ae, CumAe, and Cum%Ae for TR by interval in urine and faeces
- To identify the chemical structure of each metabolite accounting for more than 10% (in plasma) of circulating TR or metabolites in excreta (urine and faeces) that account for more than 10% of the administered radioactive dose [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Identification of the chemical structure of each paxalisib metabolite accounting for more than 10% by area under the curve (AUC) of circulating TR in plasma to identify major metabolites, and identification of each metabolite in excreta (urine and faeces) that accounts for more than 10% of the administered radioactive dose
- To explore the Cmax pharmacokinetic (PK) parameter of paxalisib following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of the PK of an oral [14C]-Paxalisib formulation by measurement of paxalisib in plasma including but not limited to Cmax parameter
- To explore the Tmax pharmacokinetic (PK) parameter of paxalisib following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of the PK of an oral [14C]-Paxalisib formulation by measurement of paxalisib in plasma including but not limited to Tmax parameter
- To explore the AUC(0-last) and AUC(0-inf) pharmacokinetic (PK) parameter of paxalisib following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of the PK of an oral [14C]-Paxalisib formulation by measurement of paxalisib in plasma including but not limited to AUC(0-last) and AUC(0-inf) parameter
- To explore the Cmax pharmacokinetic (PK) of TR following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of the PK of an oral [14C]-Paxalisib formulation by measurement of TR in plasma including but not limited to Cmax parameter
- To explore the Tmax pharmacokinetic (PK) of TR following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of the PK of an oral [14C]-Paxalisib formulation by measurement of TR in plasma including but not limited to Tmax parameter
- To explore the AUC(0-last) and AUC(0-inf) pharmacokinetic (PK) of TR following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of the PK of an oral [14C]-Paxalisib formulation by measurement of TR in plasma including but not limited to AUC(0-last) and AUC(0-inf) parameter
- To evaluate the extent of distribution of TR into blood cells [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Evaluation of whole blood:plasma concentration ratios for TR
- To provide adverse event (AE) safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
To provide safety information for paxalisib by assessing adverse events.
- To provide blood pressure vital sign safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Measuring and assessing blood pressure in standard clinical units and against reference range.
- To provide heart rate vital sign safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Measuring and assessing heart rate in standard clinical units against reference range.
- To provide oral temperature vital sign safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Measuring and assessing oral temperature in standard clinical units against reference range.
- To provide respiratory rate vital sign safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Measuring and assessing respiratory rate in standard clinical units against reference range .
- To provide electrocardiogram (ECG) safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Determination of standard ECG parameters including but not limited to PR interval, QRS duration, in standard clinical units against reference range
- To provide physical examination safety information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Assessment of standard clinical whole-body targeted (symptom-driven) physical examination including but not limited to e.g. general appearance, dermatological
- To provide hematology laboratory safety testing information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Measuring and assessing standard array of hematology parameters (e.g. white blood cell count) in standard clinical unit against reference range.
- To provide clinical chemistry laboratory safety testing information for paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Measuring and assessing standard array of clinical chemistry parameters (e.g. cholesterol) in standard clinical unit against reference range
Other Outcome Measures
- To assess the urine PK of paxalisib following administration of [14C] Paxalisib [Day 1 to Day 8 (or up to Day 10 if discharge criteria not met at Day 8)]
Determination of [14C] Paxalisib and calculation of Ae (amount excreted), CumAe (cummulative amount excreted), %Ae (fraction of dose excreted) and Cum%Ae (cummulative fraction of dose excreted) as appropriate for paxalisib in urine
Eligibility Criteria
Criteria
Inclusion Criteria:
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Healthy males.
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Aged 30 to 65 years inclusive at the time of signing informed consent.
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Body mass index (BMI) of 18.0 to 35.0 kg/m2 as measured at screening.
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Must be willing and able to communicate and participate in the whole study.
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Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per day).
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Must provide written informed consent.
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Must agree to adhere to the contraception requirements defined in study protocol.
Exclusion Criteria:
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Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1.
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Subjects who are, or are immediate family members of, a study site or sponsor employee.
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Evidence of current SARS-CoV-2 infection.
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History of any drug or alcohol abuse in the past 2 years.
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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).
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A confirmed positive alcohol breath test at screening or admission.
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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.
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Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
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Subjects with pregnant or lactating partners.
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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.
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Subjects who have been administered IMP in an ADME study in the last 12 months.
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Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
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Clinically significant abnormal clinical chemistry, haematology, or urinalysis as judged by the investigator (laboratory parameters are listed in study protocol).
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Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in study protocol)
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Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV) antibody results
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Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation.
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History of clinically significant cardiovascular, renal, hepatic, chronic respiratory disease, neurological, or psychiatric disorder, as judged by the investigator.
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History of clinically significant GI disease, especially peptic ulceration, GI bleeding, ulcerative colitis, Crohn's Disease, or Irritable Bowel Syndrome.
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Any history of pre-diabetes, diabetes mellitus (any type), or hyperglycaemia. At screening, fasting blood glucose and HbA1c must be within the normal range.
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History or presence of significant dermatological disorders or skin rashes, as judged by the investigator.
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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).
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Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
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Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
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Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood.
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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.
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Subjects who have had a COVID-19 vaccine within 72 h (3 days) before IMP administration.
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History of GI surgery (with the exception of appendectomy unless it was performed within the previous 12 months).
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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.
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Failure to satisfy the investigator of fitness to participate for any other reason.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Quotient Sciences | Nottingham | United Kingdom | NG11 6JS |
Sponsors and Collaborators
- Kazia Therapeutics Limited
- Quotient Sciences
Investigators
- Principal Investigator: Philip Evans, MBChB, MRCS, Quotient Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- KZA-0084-102
- QSC204878