Relative Bioavailability of Pyronaridine-artesunate in Tablet and Granule Formulations in Healthy Volunteers

Phase 1

Completed

Conditions: Malaria

Interventions: Drug: Pyronaridine-artesunate granules
Drug: Pyronaridine-artesunate tablets

Registration Number: NCT01868438

Lead Sponsor: Medicines for Malaria Venture

Brief Summary: The primary objective of this study is to compare the bioavailability of two formulations (tablets and granules for dispersion) of the antimalarial drug pyronaridine-artesunate \[3:1\] (Pyramax, PA) in healthy adults. The secondary objective is to compare the safety of the two PA formulations and liver function test changes following the first and second administrations.

Detailed Description: This is a Phase I, single centre, open-label, randomised, two-way cross-over study in healthy volunteers to compare the bioavailability of two formulations of pyronaridine-artesunate, in tablet and in granule formulation. The study population will include 60 healthy volunteers, comprising male and female adults aged 20 to 45 years inclusive.

The volunteers will be randomised equally on Day -1 to one of two sequences: Sequence 1 (tablets in Period 1, granules in Period 2), or Sequence 2 (granules in Period 1, tablets in Period 2). The periods will be separated by a 60-day wash-out period. Each of the two pyronaridine-artesunate formulations will be administered as a single dose of either 180:60 mg pyronaridine-artesunate tablets (3 tablets) or 60:20 mg pyronaridine-artesunate granules (9 sachets). The total dose of each formulation administered is 540:180 mg pyronaridine-artesunate.

The study duration from the first study drug administration (Day 1) through to the last follow-up will be approximately 103 days. Screening is to be performed within 28 days before Day 1. Adverse events will be monitored throughout the study (and to resolution if necessary) to assess the general safety and tolerability of the treatments.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

Inclusion Criteria

Healthy male and/or female subjects between the ages of 20 and 45 years, inclusive. (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests)
Weight between 50 kg and 80 kg and Body Mass Index (BMI) calculated using Quetelet's Index - weight(kg)/height (m2) between 18.5 to 27 kg/m2;
An informed consent document signed and dated by the subject (prior to screening and any study activities, including discontinuation of any prohibited medications)
Strictly normal values of alanine aminotransferase(ALT), aspartate aminotransferase (AST), and bilirubin, and normal or abnormal but clinically insignificant results of the other blood and urine laboratory parameters at screening.
Female subjects of non-childbearing potential [i.e., physiologically incapable of becoming pregnant, including any female who was post-menopausal (i.e., one year without menses) or who has undergone sterilization (via hysterectomy or bilateral tubal ligation)]
Female subjects of childbearing potential with a negative urine pregnancy test at screening, and a negative pregnancy blood test on admission, and who :
- agree to double barrier method of contraception for 4 weeks before first study drug administration and throughout the entire study follow up period, or
- whose partner has undergone vasectomy and has been negative for sperm for at least 6 months
Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria

Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute corrected QT interval (QTc) greater or equal to 450 milliseconds), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including head trauma)
Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins
Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab)
Seropositive HIV antibody, seropositive syphilis [Syphilis reagin test (+)]
Previous exposure to pyronaridine-artesunate (Pyramax)
Present or recent history (last two years) of tobacco abuse (≥10 cigarettes/day)
Known or suspected alcohol abuse or illicit drug use up to 5 years before the study start or positive findings on urine drug screen
Intake of alcoholic beverages or caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 48 hours before study drug administration
Intake of grapefruit, Seville oranges or products containing these from 72 hours before the start of study drug administration
Gilbert's disease
Use of over-the-counter (OTC) medications, including vitamins, analgesics, antipyretics or antacids within 7 days before study drug administration
Use of prescription medications within 14 days before the start of study drug administration or required chronic use of any prescription medication
Use of enzyme-altering agents (e.g. barbiturates, phenothiazines, cimetidine, etc.) within 30 days before the start of study drug administration
Plasma donation within 60 days before the start of study drug administration
Blood donation of 500 mL or more within 60 days before the start of study drug administration
Participation AND having had drug administration in any other clinical study within the 60 days before start of study drug administration

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Pyronaridine-artesunate tablets (Period1)	Pyronaridine-artesunate tablets	Period 1: single administration of pyronaridine-artesunate tablets: total dose 540mg pyronaridine + 180mg artesunate. Period 2: cross-over to single administration of pyronaridine-artesunate granules: total dose 540mg pyronaridine + 180mg artesunate.
Pyronaridine-artesunate granules (Period 1)	Pyronaridine-artesunate granules	Period 1: single administration of pyronaridine-artesunate granules: total dose 540mg pyronaridine + 180mg artesunate. Period 2: cross-over to single administration of pyronaridine-artesunate tablets: total dose 540mg pyronaridine + 180mg artesunate.
Pyronaridine-artesunate granules (Period 1)	Pyronaridine-artesunate tablets	Period 1: single administration of pyronaridine-artesunate granules: total dose 540mg pyronaridine + 180mg artesunate. Period 2: cross-over to single administration of pyronaridine-artesunate tablets: total dose 540mg pyronaridine + 180mg artesunate.
Pyronaridine-artesunate tablets (Period1)	Pyronaridine-artesunate granules	Period 1: single administration of pyronaridine-artesunate tablets: total dose 540mg pyronaridine + 180mg artesunate. Period 2: cross-over to single administration of pyronaridine-artesunate granules: total dose 540mg pyronaridine + 180mg artesunate.

Primary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA)	First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103)	Pharmacokinetic blood sampling for first or second intervention dose

Secondary Outcome Measures

Name	Time	Method
Safety Evaluation - Summary of Adverse Events	End of study (Day 103)
Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA	First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103)	Pharmacokinetic blood sampling for first or second intervention dose