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

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, receiving study drug over the course of 7 days.

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. 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.

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

Conditions
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Malaria, Glucose 6 Phosphate Dehydrogenase Deficiency

Intervention / Treatment
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* Drug: RPQ
* Drug: SPQ
* Drug: Primaquine Phosphate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Crossover Assignment
Interventional 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RPQ (-) enantiomer<br>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 | Drug: RPQ<br>* The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.<br>* Other names: R-(-) Enantiomer of Primaquine Phosphate;|
| Experimental: SPQ (+) enantiomer<br>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 | Drug: SPQ<br>* The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.<br>* Other names: S-(+) Enantiomer of Primaquine Phosphate;|
| Active Comparator: Primaquine Phosphate<br>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 | Drug: Primaquine Phosphate<br>* The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.<br>* Other names: Racemic Primaquine;|
| Placebo Comparator: Placebo<br>Cohort 1 will receive placebo (4A) capsules everyday for seven days Cohort 2 will receive placebo (4A) capsules everyday for seven days | Drug: Placebo<br>* The study will compare the individual enantiomers of primaquine - R- (-)-PQ, S-(+)-PQ, and Placebo along with the racemic version.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Methemoglobin concentration in blood from baseline | Change in Methemoglobin concentration in blood from baseline (% hemoglobin) | Days 0, 3, 5, 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primaquine Plasma concentration, ng/mL | Plasma concentrations of parent drug | Days 0, 3, 5, 7 | 
| Carboxy- Primaquine Plasma concentration, ng/mL | Plasma concentrations of carboxy-primaquine metabolite | Days 0, 3, 5, 7 | 
| Primaquine N-carbamoyl-glucuronide Plasma concentration, ng/mL | Plasma concentrations of Primaquine N-carbamoyl-glucuronide metabolite | Days 0, 3, 5, 7 | 
| Primaquine Orthoquinone Plasma concentration, ng/mL | Plasma concentrations of Primaquine Orthoquinone metabolite | Days 0, 3, 5, 7 | 
| Change in Hematocrit (%) Compared to baseline | Change in Hematocrit (%) Compared to baseline | Days 0, 3, 5, 7 | 
| Change in Hemoglobin (g/dL) Compared to baseline | Change in Hemoglobin (g/dL) Compared to baseline | Days 0, 3, 5, 7 | 
| Change in AST (U/L) Compared to baseline | Change in Aspartate aminotransferase (U/L) Compared to baseline; used to monitor liver function | Days 0, 3, 5, 7 | 
| Change in ALT (U/L) Compared to baseline | Change in Alanine aminotransferase (U/L) Compared to baseline; used to monitor liver function | Days 0, 3, 5, 7 | 
| 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 | Days 0, 3, 5, 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemolysis, Primaquine, Pharmacokinetics