Human Mass Balance Study of Pyronaridine

Study Overview
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Brief Summary
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The combination of pyronaridine and artesunate is an antimalarial therapy in development. This mass balance study is intended to determine the rate and extent of excretion of total radioactivity in urine and feces following administration of a single oral micro-dose of 14C-pyronaridine in humans.

Detailed Description
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This is a monocenter, open-label, non-placebo-controlled, single-group, single-dose study. Six male subjects will receive a single dose of Pyronaridine 720 mg orally administered together with 14C-Pyronaridine (approx. 100 µg, 800 nCi (29600 Bq)). Safety measurements (12-lead ECG, vital signs, blood chemistry and haematology) and adverse events will be monitored throughout the study. Subjects will come to the clinic the evening before the dosing of Pyronaridine. After the drug intake at day 1, subjects will have regular in-house periods for specimen collection up to 87 days after the drug administration. Blood, feces and urine will be collected during the hospitalisation periods. Samples will be analyzed for radioactivity by Accelerator Mass Spectrometry (AMS).

Official Title
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A Human Mass Balance Study of Pyronaridine Using Accelerator Mass Spectrometry

Conditions
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Malaria

Intervention / Treatment
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* Drug: 14C-labeled Pyronaridine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects between the ages of 40 and 55 years with a body weight between 60 and 90 kg and a body mass index calculated using Quetelet's Index - weight (kg)/height2 (m2) between 18.5 - 30.0 Signed and dated written informed consent form (ICF) before undergoing any study related activities, including discontinuation of any prohibited medications Medically normal subjects with no significant abnormal findings at the screening physical examination as evaluated by the investigator Strictly normal values of ALT, AST and bilirubin and normal or abnormal and clinically insignificant results (if agreed by the Investigator and the Sponsor on a case by case evaluation) of the other blood and urine laboratory parameters at screening All sexually active male subjects and their partners are willing to undergo contraception as follows: All male subjects, including those who are sterilised (i.e., vasectomy), should use a condom. Their female partner must also use at least 1 of the medically acceptable forms of contraceptives listed below. Male subjects must not donate sperm or have unprotected sex during the study and until 87 days after taking the dose of investigational product. Medically acceptable contraceptives for this study are: Condoms in addition to: Intrauterine devices Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring) Diaphragms with spermicidal cream or gel Cervical cap with spermicidal cream or gel Spermicidal foam The ability to understand the requirements of the study and willingness to comply with all study procedures Exclusion Criteria: Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute QTc interval greater or equal to 450 mseconds), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other clinical abnormality Known history of hypersensitivity, allergic or adverse reactions to Pyronaridine Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab) Seropositive HIV antibody Previous participation in any clinical study with Pyramax Presence or recent history (last two years) of tobacco abuse (≥10 cigarettes/day) Known or suspected alcohol abuse or illicit drug use in the last 10 years before the study start or positive findings on urine drug screen Intake of grapefruit and grapefruit juice alcoholic beverages or caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 48 hours before study drug administration Use of over-the-counter (OTC) medications, including vitamins, analgesics, or antacids, 1 week before the study start Use of prescription medications 14 days before the study start or required chronic use of any prescription medication Use of enzyme-altering agents (e.g., barbiturates, phenothiazines, cimetidine, etc.) within 30 days or 5 half lives, whichever the longer, before the study start Plasma donation 1 month before the study start Blood donation of 450 mL or more in the last 3 months before the study start Participation in other clinical trials during the previous month in which an investigational drug or a commercially available drug was tested Exposure to artificial ionizing radiation in the last 12 months (e.g., x-ray investigation, isotope studies)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyronaridine<br>All subjects will receive a single dose of Pyronaridine | Drug: 14C-labeled Pyronaridine<br>* Single dose of 720 mg Pyronaridine together with 14C-Pyronaridine (approx. 100 µg, 800 nCi).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of 14C-Pyronaridine Total Radioactivity in Urine | Radioactivity recovery in urine as a percent of the administered dose. Continuous collection of samples was performed through 168 hours post-dose, with intermittent 48 hour collections occurring thereafter | 2064 hours | 
| Analysis of 14C-Pyronaridine Total Radioactivity in Feces | Radioactivity recovery in feces as a percent of the administered dose. Continuous collection of samples was performed through 168 hours post-dose, with intermittent 48 hour collections occurring thereafter | 2064 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Radioactivity in Blood: AUC0-t, AUC0-∞ | Pharmacokinetic Parameters: AUC0-t: area under the plasma concentration-time curve from Hour 0 through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was collected AUC0-∞: area under the plasma concentration-time curve from Hour 0 to infinity PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose | 42 days | 
| Total Radioactivity in Blood: Cmax | Pharmacokinetic Parameters: Cmax: maximum observed peak observed concentration PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose | 42 days | 
| Total Radioactivity in Blood: Half-life, Tmax | Pharmacokinetic Parameters: Half-life: computed as ln (2) / Kel Tmax: time to maximum concentration PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mass Balance, Accelerated Mass Spectrometry (AMS), microdose, Focus of the study: ADME