Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers, Study 1

Study Overview
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Brief Summary
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To investigate the comparative tolerability, metabolism and pharmacokinetics of individual enantiomers of PQ in healthy human volunteers. The specific aim is the comparative evaluation of the metabolism, pharmacokinetic behavior, and tolerability of the isomers of PQ (RPQ and SPQ and the racemic mixture RSPQ) in normal healthy human volunteers.

Detailed Description
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The primary objective of this project is to investigate the comparative tolerability, metabolism and pharmacokinetics of individual enantiomers of PQ in healthy human volunteers. The overall approach is as follows: in 36 healthy volunteers with documented normal G6PD activity, we will administer a single oral dose of RPQ, SPQ, or RSPQ. At various times after dosing, we will draw blood samples, in which we will record the plasma levels of the parent drugs, along with plasma and urinary metabolites. The comparative pharmacokinetics, tolerability and hematological effects of these two enantiomers and the racemate will be assessed.

Official Title
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Development of Safer Drugs for Malaria in U.S. Troops, Civilian Personnel, and Travelers: Clinical Evaluation of Primaquine Enantiomer

Conditions
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Malaria

Intervention / Treatment
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* Drug: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (18-60 years of age) Informed consent Healthy Exclusion Criteria: Known history of liver, kidney or hematological disease; known history of cardiac disease, arrhythmia, QT prolongation; Autoimmune disorder; Report of an active infection; Evidence of G6PD deficiency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 ( Primaquine Low Dose)<br>Interventions: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine A single center, prospective, cross-over, randomized phase 1 trial. Thirty-six participants, enrolled into a two cohort pharmacokinetic study evaluating two dose levels of primaquine isomers. Cohort 1 (Low Dose Level)- single dose of 15 mg of S-Primaquine and 15 mg of R-Primaquine compared to 30 mg RS-Primaquine over 24 hours. Participants will cross-over after a one week wash-out period. | Drug: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine<br>* Cohort 1: Eighteen individuals (6 per group) Cohort 2: Eighteen individuals (6 per group) Group 1-15 mg of S-Primaquine followed by one-week washout, 15 mg of R-Primaquine followed by one week washout, and 30 mg of RS-Primaquine. Group 2- 15 mg of R-Primaquine followed by one-week washout, 30 mg of RSPQ followed by one week washout, and 15 mg of SPQ. Group 3- 30 mg of RS-Primaquine followed by one week washout,15 mg of SPQ followed by a one week washout, and 15 mg of RPQ.<br>* Other names: Primaquine;|
| Experimental: Cohort 2 (Primaquine High Dose)<br>Interventions: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine A single center, prospective, cross-over, randomized phase 1 trial. Thirty-six participants, enrolled into a two cohort pharmacokinetic study evaluating two dose levels of primaquine isomers. Cohort 2 (High Dose Level)-single dose of 22.5 mg of S-Primaquine and 22.5 mg of R-Primaquine compared to 45 mg RS-Primaquine over 24 hours. Participants will cross-over among the treatment arms following a one week wash-out period between each. | Drug: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine<br>* Cohort 1: Eighteen individuals (6 per group) Cohort 2: Eighteen individuals (6 per group) Group 1-15 mg of S-Primaquine followed by one-week washout, 15 mg of R-Primaquine followed by one week washout, and 30 mg of RS-Primaquine. Group 2- 15 mg of R-Primaquine followed by one-week washout, 30 mg of RSPQ followed by one week washout, and 15 mg of SPQ. Group 3- 30 mg of RS-Primaquine followed by one week washout,15 mg of SPQ followed by a one week washout, and 15 mg of RPQ.<br>* Other names: Primaquine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome: Plasma concentration of parent primaquine and carboyprimaquine following a single dose treatment with primaquine (racemate or enantiomers) not to exceed 45 mg | This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers | between 0-24 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) for primaquine up to 24 hours after the primaquine administration | This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers | between 0-24 hours | 
| Maximum concentration (Cmax) for primaquine up to 24 hours after the primaquine administration | This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers | between 0-24 hours | 
| Area Under Curve (AUC) for carboxyprimaquine, the major plasma metabolite of primaquine, up to 24 hours after primaquine administration | This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers | between 0-24 hours | 
| Maximum concentration of carboxyprimaquine, the major plasma metabolite of primaquine, up to 24 hours after primaquine administration | This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers | between 0-24 hours | 
| Maximum concentration of selected metabolites primaquine (other than carboxyprimaquine) up to 24 hours after primaquine administration | This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers. The exact nature of these metabolites will be determined from previous animal and human studies | between 0-24 hours | 
| hemoglobin and methemoglobin levels in the blood after administration of primaquine | To monitor hemoglobin and methemoglobin levels in normal human volunteers treated with single dose of primaquine not to exceed 45 mg | 0-72 hours | 
| Genotyping of Cytochrome P-450 (CYP) | To determine correlation between metabolism of primaquine and CYP 2D6 genotype | day 0 |