Excretion Balance, PK and Metabolism of a Single Oral Dose of [14C]PCO371

A Phase I, Single-Center, Open-Label Study Investigating the Excretion Balance, Pharmacokinetics (PK) and Metabolism of a Single Oral Dose of [14C]PCO371 and PK of an Intravenous (IV) Tracer of [14C]PCO371 in Healthy Male Subjects

This is a Phase I single center, open-label, non-randomized study in healthy male subjects, designed to evaluate the mass balance recovery, PK, metabolism and absolute bioavailability of single oral doses of PCO371. It is planned to enroll 12 subjects, with 6 subjects in each of 2 study parts. Subjects in Part 1 will receive a single oral dose of [14C]PCO371 Oral Solution. Subjects in Part 2 will receive a single oral dose of PCO371 capsules, followed by a single intravenous infusion of [14C]PCO371 Solution for Infusion over 10 min, starting 2 h post-oral dose. The study parts may be dosed in any order for logistical reasons (e.g. Part 2 may be dosed before Part 1). No subject will be permitted to take part in both study parts.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: [14C]PCO371; Drug: [14C]PCO371; Drug: PCO371

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • UK
    • Nottingham, UK, United Kingdom, NG11 6JS
      • Quotient Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Healthy males
2. Aged 40 to 60 years inclusive at the time of signing informed consent.
3. Body mass index (BMI) of 18.5 to 30.0 kg/m2 as measured at screening.
4. Must be willing and able to communicate and participate in the whole study.
5. Subjects must have regular bowel movements (i.e. average stool production of >=1 and <=3 stools per day).
6. Must provide written informed consent.
7. Must agree to adhere to the contraception requirements.
8. Subjects must regularly consume 2 or more units of alcohol per week.

Exclusion Criteria:

1. Subjects who have taken any experimental (non-approved) drug (including placebo) either within 90 days before the administration of the study drug, or 6 times the T1/2 of the experimental drug, whichever is longer.
2. Subjects who have previously been administered IMP in this study. Subjects are not permitted to be dosed in both Part 1 and Part 2 of the study.
3. Subjects who have been administered IMP in any 14C-labelled ADME in the last 12 months.
4. 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.
5. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study.
6. Subjects who do not have suitable veins for multiple venipunctures / cannulation as assessed by the investigator or delegate at screening.
7. Clinically significant abnormal clinical chemistry, hematology, coagulation or urinalysis as judged by the investigator at screening or admission.
8. Abnormal (outside of reference range) serum calcium or corrected calcium as measured at admission or screening.
9. Elevated (> 2.5 × upper limit of normal [ULN]) alkaline phosphatase at admission or screening. Subjects with Gilbert's syndrome or elevated (above the ULN) aspartate aminotransferase (AST), ALT or total bilirubin at admission or screening.
10. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results.
11. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of <60 mL/min using the Cockcroft-Gault equation.
12. Confirmed positive drugs of abuse test result.
13. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, immunologic, metabolism, endocrine, neurological or psychiatric disorder, as judged by the investigator, blood dyscrasia, risk factors for osteosarcoma as judged by the investigator.
14. Evidence or any history of active diseases that might affect calcium, bone metabolism, or calcium-phosphate homeostasis.
15. Use of anti-coagulants (e.g. heparins, warfarin, and thrombolytic agents), anti-platelet medications (e.g. argatroban and ticlopidine), nonsteroidal anti-inflammatory drugs and aspirin within 2 weeks (or within 6 times the T1/2 of the drug, whichever is longer) prior to study drug administration.
16. Subjects who have taken any inducers of CYP3A4, P glycoprotein (e.g. St. John's wort), or BCRP within 1 month prior to study drug administration, or taken any inhibitors of CYP3A4, P-glycoprotein, or BCRP (including herbal products, diets, and drinks e.g. tonic water) within 2 weeks prior to study drug administration (or within 6 times the T1/2 of the drugs mentioned above, whichever is longer).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mass Balance; Subjects will receive a single oral dose of [14C]PCO371 Oral Solution.	Drug: [14C]PCO371; [14C]PCO371 Oral solution; Drug: [14C]PCO371; [14C]PCO371 Solution for infusion
EXPERIMENTAL: Absolute Bioavailability and Mass Balance; Subjects will receive a single oral dose of PCO371 capsules, followed by a single IV infusion of [14C]PCO371 over 10 min, starting 2 h post-oral dose.	Drug: [14C]PCO371; [14C]PCO371 Oral solution; Drug: [14C]PCO371; [14C]PCO371 Solution for infusion; Drug: PCO371; PCO371 Capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mass balance data for [14C]PCO371 Oral solution in urine	Amount of total radioactivity excreted in urine(Ae(urine)) and Ae(urine) expressed as a percentage of the radioactive dose administered (%Ae(urine)), cumulative amount of total radioactivity excreted in urine (CumAe(urine)) and CumAe(urine)expressed as a percentage of the radioactive dose administered (Cum%Ae(urine)) following oral administration of [14C]PCO371 Oral Solution.	1 week
Mass balance data for [14C]PCO371 Oral solution in feces	Amount of total radioactivity excreted in feces(Ae(feces)) and Ae(feces) expressed as a percentage of the radioactive dose administered (%Ae(feces)), cumulative amount of total radioactivity excreted in feces (CumAe(feces)) and CumAe(feces)expressed as a percentage of the radioactive dose administered (Cum%Ae(feces)) following oral administration of [14C]PCO371 Oral Solution.	5 weeks
Mass balance data for [14C]PCO371 Oral solution in urine and feces combined	Amount of total radioactivity excreted in urine and feces combined(Ae(total)) and Ae(total) expressed as a percentage of the radioactive dose administered (%Ae(total)), cumulative amount of total radioactivity excreted in urine and feces combined (CumAe(total)) and CumAe(total)expressed as a percentage of the radioactive dose administered (Cum%Ae(total)) following oral administration of [14C]PCO371 Oral Solution.	5 weeks
Absolute bioavailability (F) for PCO371	Time of maximum observed concentration for PCO371 and a metabolite in plasma and for total radioactivity in plasma and whole blood following oral administration of [14C]PCO371 Oral Solution	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic data for [14C]PCO371 Oral Solution; Tmax	Time of maximum observed concentration for PCO371 and a metabolite in plasma and for total radioactivity in plasma and whole blood following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; Cmax	Maximum observed concentration for PCO371 and a metabolite in plasma and for total radioactivity in plasma and whole blood following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; AUC(0-last)	Area under the curve from time 0 to the time of last measurable concentration for PCO371 and a metabolite in plasma and for total radioactivity in plasma and whole blood following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; AUC(0-inf)	Area under the curve from time 0 extrapolated to infinity for PCO371 and a metabolite in plasma and for total radioactivity in plasma and whole blood following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; T1/2	Terminal elimination half-life for PCO371 and a metabolite in plasma and for total radioactivity in plasma and whole blood following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; Cmax ratio	Ratio of PCO371: total radioactivity and ratio of a metabolite: total radioactivity based on Cmax following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; AUC ratio	Ratio of whole blood: plasma total radioactivity based on Cmax following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; B:P Cmax ratio	Ratio of whole blood:plasma total radioactivity based on Cmax following oral administration of [14C]PCO371 Oral Solution	1 week
Pharmacokinetic data for [14C]PCO371 Oral Solution; B:P AUC ratio	Ratio of whole blood:plasma total radioactivity based on AUC following oral administration of [14C]PCO371 Oral Solution	1 week
Metabolite profiling of plasma, urine and feces	The chemical structure of each metabolite accounting for >=5% of circulating radioactivity in plasma and accounting for >=5% of the dose in the urine and feces	1 week
Intravenous pharmacokinetic data for [14C]PCO371 Solution for Infusion; C0	Concentration at end of infusion of [14C]PCO371 and total radioactivity in plasma following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Intravenous pharmacokinetic data for [14C]PCO371 Solution for Infusion; AUC(0-last)	Area under the curve from time 0 to the time of last measurable concentration of [14C]PCO371 and total radioactivity in plasma following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Intravenous pharmacokinetic data for [14C]PCO371 Solution for Infusion; AUC(0-inf)	Area under the curve from time 0 extrapolated to infinity of [14C]PCO371 and total radioactivity in plasma following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Intravenous pharmacokinetic data for [14C]PCO371 Solution for Infusion; T1/2	Terminal elimination half-life of [14C]PCO371 and total radioactivity in plasma following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Intravenous pharmacokinetic data for [14C]PCO371 Solution for Infusion; CL	Total body clearance calculated after a single IV administration of [14C]PCO371 in plasma following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Intravenous pharmacokinetic data for [14C]PCO371 Solution for Infusion; Vz	Volume of distribution based on the terminal phase calculated using AUC(0-inf) after a single IV administration of [14C]PCO371 in plasma following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Oral pharmacokinetic data for PCO371 capsule; Tmax	Time of maximum observed concentration for plasma concentration of PCO371 and a metabolite following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Oral pharmacokinetic data for PCO371 capsule; Cmax	Maximum observed concentration for plasma concentration of PCO371 and a metabolite following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Oral pharmacokinetic data for PCO371 capsule; AUC(0-last)	Area under the curve from time 0 to the time of last measurable concentration for plasma concentration of PCO371 and a metabolite following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Oral pharmacokinetic data for PCO371 capsule; AUC(0-inf)	Area under the curve from time 0 extrapolated to infinity for plasma concentration of PCO371 and a metabolite following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Oral pharmacokinetic data for PCO371 capsule; T1/2	Terminal elimination half-life for plasma concentration of PCO371 and a metabolite following oral dose of PCO371 capsules and intravenous infusion of [14C]PCO371 Solution for Infusion.	1 week
Mass balance data for [14C]PCO371 Solution for Infusion in urine	Cumulative amount of total radioactivity excreted in urine expressed as a percentage of the radioactive dose administered (Cum%Ae(urine)) and cumulative amount of [14C]PCO371 excreted in urine expressed as a percentage of the [14C]PCO371 dose administered (Cum%Ae([14C]PCO371 urine))	1 week
Mass balance data for [14C]PCO371 Solution for Infusion in feces	Cumulative amount of total radioactivity excreted in feces expressed as a percentage of the radioactive dose administered (Cum%Ae(feces)) and cumulative amount of [14C]PCO371 excreted in feces expressed as a percentage of the [14C]PCO371 dose administered (Cum%Ae([14C]PCO371 feces))	5 weeks
Safety data for PCO371; Adverse event monitoring	Incidence and severity of adverse events	6 weeks
Safety data for PCO371; Incidence of laboratory abnormalities	Incidence of laboratory abnormalities, based on clinical laboratory tests ( i.e. hematology, clinical chemistry, coagulation and urinalysis test results)	6 weeks
Safety data for PCO371; 12-lead ECGs (Ventricular Rate)	Abnormality in Electrocardiograms (ECGs) Interpretation based on Ventricular Rate	6 weeks
Safety data for PCO371; 12-lead ECGs (PR interval)	Abnormality in Electrocardiograms (ECGs) Interpretation based on PR interval	6 weeks
Safety data for PCO371; 12-lead ECGs (QRS Duration)	Abnormality in Electrocardiograms (ECGs) Interpretation based on QRS Duration	6 weeks
Safety data for PCO371; 12-lead ECGs (QT interval)	Abnormality in Electrocardiograms (ECGs) Interpretation based on QT interval	6 weeks
Safety data for PCO371; 12-lead ECGs (QRS Axis)	Abnormality in Electrocardiograms (ECGs) Interpretation based on QRS Axis	6 weeks
Safety data for PCO371; 12-lead ECGs (QTcF interval)	Abnormality in Electrocardiograms (ECGs) Interpretation based on QTcF interval	6 weeks
Safety data for PCO371; 12-lead ECGs (Rhythm)	Abnormality in Electrocardiograms (ECGs) Interpretation based on Rhythm	6 weeks
Safety data for PCO371; Vital signs (Systolic blood pressure)	Abnormality in Systolic blood pressure	6 weeks
Safety data for PCO371; Vital signs (Diastolic blood pressure)	Abnormality in Diastolic blood pressure	6 weeks
Safety data for PCO371; Vital signs (Heart Rate)	Abnormality in Heart Rate	6 weeks
Safety data for PCO371; Vital signs (Oral temperature)	Abnormality in Oral temperature	6 weeks
Safety data for PCO371; Presense of abnormalities in Physical examinations	Abnormality in Physical examination findings	6 weeks

Collaborators and Investigators

• Sponsor: Chugai Pharmaceutical
• Investigators: Study Director: Chugai Pharma Europe Ltd., clinical-trials@chugai-pharm.co.jp

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 25, 2020
• Primary Completion (ACTUAL): December 30, 2020
• Study Completion (ACTUAL): December 30, 2020

Study Registration Dates

• First Submitted: November 11, 2020
• First Submitted That Met QC Criteria: November 24, 2020
• First Posted (ACTUAL): December 2, 2020

Study Record Updates

• Last Update Posted (ACTUAL): March 1, 2021
• Last Update Submitted That Met QC Criteria: February 25, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Other Study ID Numbers: PCO006EU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). For further details on Chugai's Data Sharing Policy and how to request access to related clinical study documents, see here (www.chugai-pharm.co.jp/english/profile/rd/ctds_request.html).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No