Primaquine Enantiomers in G6PD Deficient Human Volunteers

Study Overview
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Brief Summary
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This study is a single center, prospective, cross-over phase 1 trial. Eighteen subjects will be enrolled in the study evaluating the metabolism, pharmacokinetic behavior and tolerability of primaquine enantiomers and placebo over the course of 5 days.

Detailed Description
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Each subject will receive a 15 mg dose of one enantiomer (SPQ or RPQ or Placebo) daily for up to 5 days, with careful monitoring of hematological parameters before and after each dose. In addition to the general CMP14 safety criteria, any subject who displays a fractional hemoglobin drop of 15% below his/her baseline value, then drug administration will stop (e.g. for baseline Hgb of 14 g/dL, if there is at any point a decrease of 2.1 g/dL). Hematocrit will be similarly monitored, with proportional stop criteria. Elevation in total bilirubin to 2.0 mg/dL or greater will also be used as a stopping criterion. After stopping drug administration (5 days or whenever stop criteria are met), subjects will have a 3-week washout period, and the study repeated with the other enantiomer, and similarly with Placebo.

Official Title
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Metabolism and Pharmacokinetics of Primaquine Enantiomers in G6PD Deficient Human Volunteers Receiving a Five Day Dose Regimen

Conditions
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G6PD Deficiency

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: G6PD deficient, otherwise normal healthy adults aged 18 to 65 Exclusion Criteria: Known history of liver, kidney or hematological disease (other than G6PD deficiency) Known history of cardiac disease, non-sinus rhythm arrhythmia or QT prolongation Autoimmune disorders Report of an active infection Subject 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RPQ (-) enantiomer<br>Cohort 1 will receive 15mg of RPQ every day for 5 days. Cohort 2 will receive 22.5 mg of RPQ every day for five days. | Drug: RPQ<br>* The study will compare the individual enantiomers of Primaquine -R-(-)-PQ, S-(+)-PQ, and Placebo.<br>* Other names: R-(-) Enantiomer of Primiquine Phosphate;|
| Experimental: SPQ (+) enantiomer<br>Cohort 1 will receive 15mg of SPQ every day for 5 days. Cohort 2 will receive 22.5 mg of SPQ every day for five days. | Drug: SPQ<br>* The study will compare the individual enantiomers of Primaquine -R-(-)-PQ, S-(+)-PQ, and Placebo.<br>* Other names: S-(+) Enantiomer of Primaquine Phosphate;|
| Placebo Comparator: Placebo<br>Cohort 1 will receive placebo capsules every day for 5 days. Cohort 2 will receive placebo capsules every day for five days. | Drug: Placebo<br>* The study will compare the individual enantiomers of Primaquine -R-(-)-PQ, S-(+)-PQ, and Placebo.<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 | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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G6PD, Hemolysis, Primaquine, Pharmacokinetics, Malaria