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Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers Receiving a Seven Day Dose Regimen

Primary Purpose

Malaria, Glucose 6 Phosphate Dehydrogenase Deficiency

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
RPQ
SPQ
Primaquine Phosphate
Placebo
Sponsored by
University of Mississippi, Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Malaria focused on measuring Hemolysis, Primaquine, Pharmacokinetics

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Normal, healthy adults aged 18 to 65 years

Exclusion Criteria:

  • Known history of liver, kidney or hematological disease
  • Known history of cardiac disease, Non Sinus Rhythm arrhythmia or QT prolongation
  • Autoimmune disorders
  • Report of an active infection
  • Evidence of G6PD deficiency
  • Participant is pregnant or breast-feeding, or is expecting to conceive during the study.

Sites / Locations

  • University of Mississippi

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Active Comparator

Placebo Comparator

Arm Label

RPQ (-) enantiomer

SPQ (+) enantiomer

Primaquine Phosphate

Placebo

Arm Description

Cohort 1 will receive 15 mg of RPQ (3A) every day for 7 days Cohort 2 will receive 22.5 mg of RPQ (3A) every day for 7 days

Cohort 1 will receive 15 mg of SPQ (2A) every day for 7 days Cohort 2 will receive 22.5 mg of SPQ (2A) every day for 7 days

Cohort 1 will receive 30 mg of RSPQ (1A) every day for 7 days Cohort 2 will receive 45 mg of RSPQ (1A) every day for 7 days

Cohort 1 will receive placebo (4A) capsules everyday for seven days Cohort 2 will receive placebo (4A) capsules everyday for seven days

Outcomes

Primary Outcome Measures

Change in Methemoglobin concentration in blood from baseline
Change in Methemoglobin concentration in blood from baseline (% hemoglobin)

Secondary Outcome Measures

Primaquine Plasma concentration, ng/mL
Plasma concentrations of parent drug
Carboxy- Primaquine Plasma concentration, ng/mL
Plasma concentrations of carboxy-primaquine metabolite
Primaquine N-carbamoyl-glucuronide Plasma concentration, ng/mL
Plasma concentrations of Primaquine N-carbamoyl-glucuronide metabolite
Primaquine Orthoquinone Plasma concentration, ng/mL
Plasma concentrations of Primaquine Orthoquinone metabolite
Change in Hematocrit (%) Compared to baseline
Change in Hematocrit (%) Compared to baseline
Change in Hemoglobin (g/dL) Compared to baseline
Change in Hemoglobin (g/dL) Compared to baseline
Change in AST (U/L) Compared to baseline
Change in Aspartate aminotransferase (U/L) Compared to baseline; used to monitor liver function
Change in ALT (U/L) Compared to baseline
Change in Alanine aminotransferase (U/L) Compared to baseline; used to monitor liver function
Change in Total Bilirubin (mg/dL) Compared to baseline
Change in Total Bilirubin (mg/dL) Compared to baseline; used to monitor liver function and red cell integrity

Full Information

First Posted
May 14, 2018
Last Updated
May 13, 2019
Sponsor
University of Mississippi, Oxford
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1. Study Identification

Unique Protocol Identification Number
NCT03934450
Brief Title
Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers Receiving a Seven Day Dose Regimen
Official Title
Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers Receiving a Seven Day Dose Regimen
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
August 17, 2018 (Actual)
Primary Completion Date
May 1, 2019 (Actual)
Study Completion Date
May 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Mississippi, Oxford

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
To investigate the comparative tolerability, metabolism and pharmacokinetics of individual enantiomers of PQ in healthy human volunteers, receiving study drug over the course of 7 days.
Detailed Description
The primary objective of this project is to investigate the comparative tolerability, metabolism and pharmacokinetics of individual enantiomers of PQ in healthy human volunteers. Based on the results of this study, if one enantiomer seems to show a better safety profile (in terms of hematological effects), an analogous study will be carried out in G6PD deficient individuals (under a separate protocol). The studies are primarily aimed at understanding the tolerability and safety of the enantiomers in G6PD deficiency. If one shows a better safety profile, ultimately the evaluation of its efficacy will be required.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Glucose 6 Phosphate Dehydrogenase Deficiency
Keywords
Hemolysis, Primaquine, Pharmacokinetics

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
This study is a single center, prospective, cross-over phase 1 trial. Thirty-six participants will be enrolled into a two Cohort pharmacokinetic study evaluating the metabolism, pharmacokinetic behavior and tolerability of two dose levels (low/high) of primaquine enantiomers (and placebo) over the course of 7 days. Placebo will be added in order to assess tolerability of enantiomers. Placebo control is needed in non-drug related clinical responses.
Masking
Participant
Masking Description
Participants will not be able to know the sequence of the drug adminstration
Allocation
Non-Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RPQ (-) enantiomer
Arm Type
Experimental
Arm Description
Cohort 1 will receive 15 mg of RPQ (3A) every day for 7 days Cohort 2 will receive 22.5 mg of RPQ (3A) every day for 7 days
Arm Title
SPQ (+) enantiomer
Arm Type
Experimental
Arm Description
Cohort 1 will receive 15 mg of SPQ (2A) every day for 7 days Cohort 2 will receive 22.5 mg of SPQ (2A) every day for 7 days
Arm Title
Primaquine Phosphate
Arm Type
Active Comparator
Arm Description
Cohort 1 will receive 30 mg of RSPQ (1A) every day for 7 days Cohort 2 will receive 45 mg of RSPQ (1A) every day for 7 days
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Cohort 1 will receive placebo (4A) capsules everyday for seven days Cohort 2 will receive placebo (4A) capsules everyday for seven days
Intervention Type
Drug
Intervention Name(s)
RPQ
Other Intervention Name(s)
R-(-) Enantiomer of Primaquine Phosphate
Intervention Description
The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.
Intervention Type
Drug
Intervention Name(s)
SPQ
Other Intervention Name(s)
S-(+) Enantiomer of Primaquine Phosphate
Intervention Description
The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.
Intervention Type
Drug
Intervention Name(s)
Primaquine Phosphate
Other Intervention Name(s)
Racemic Primaquine
Intervention Description
The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.
Primary Outcome Measure Information:
Title
Change in Methemoglobin concentration in blood from baseline
Description
Change in Methemoglobin concentration in blood from baseline (% hemoglobin)
Time Frame
Days 0, 3, 5, 7
Secondary Outcome Measure Information:
Title
Primaquine Plasma concentration, ng/mL
Description
Plasma concentrations of parent drug
Time Frame
Days 0, 3, 5, 7
Title
Carboxy- Primaquine Plasma concentration, ng/mL
Description
Plasma concentrations of carboxy-primaquine metabolite
Time Frame
Days 0, 3, 5, 7
Title
Primaquine N-carbamoyl-glucuronide Plasma concentration, ng/mL
Description
Plasma concentrations of Primaquine N-carbamoyl-glucuronide metabolite
Time Frame
Days 0, 3, 5, 7
Title
Primaquine Orthoquinone Plasma concentration, ng/mL
Description
Plasma concentrations of Primaquine Orthoquinone metabolite
Time Frame
Days 0, 3, 5, 7
Title
Change in Hematocrit (%) Compared to baseline
Description
Change in Hematocrit (%) Compared to baseline
Time Frame
Days 0, 3, 5, 7
Title
Change in Hemoglobin (g/dL) Compared to baseline
Description
Change in Hemoglobin (g/dL) Compared to baseline
Time Frame
Days 0, 3, 5, 7
Title
Change in AST (U/L) Compared to baseline
Description
Change in Aspartate aminotransferase (U/L) Compared to baseline; used to monitor liver function
Time Frame
Days 0, 3, 5, 7
Title
Change in ALT (U/L) Compared to baseline
Description
Change in Alanine aminotransferase (U/L) Compared to baseline; used to monitor liver function
Time Frame
Days 0, 3, 5, 7
Title
Change in Total Bilirubin (mg/dL) Compared to baseline
Description
Change in Total Bilirubin (mg/dL) Compared to baseline; used to monitor liver function and red cell integrity
Time Frame
Days 0, 3, 5, 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Normal, healthy adults aged 18 to 65 years Exclusion Criteria: Known history of liver, kidney or hematological disease Known history of cardiac disease, Non Sinus Rhythm arrhythmia or QT prolongation Autoimmune disorders Report of an active infection Evidence of G6PD deficiency Participant is pregnant or breast-feeding, or is expecting to conceive during the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Larry Walker, Phd
Organizational Affiliation
University of Mississippi Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Mississippi
City
University
State/Province
Mississippi
ZIP/Postal Code
38677
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers Receiving a Seven Day Dose Regimen

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