The purpose of this study is to determine the highest tolerable dose of primaquine within 0.75 mg/kg. A tolerable dose is defined as one in which: * Two or fewer participants (\< 30%) experience hemolysis; * No participant experiences a drug-related serious adverse event; and * No participant requires a blood transfusion.
Purpose: The purpose of this study is to determine the highest tolerable dose of primaquine within 0.75 mg/kg. A tolerable dose is defined as one in which: * Two or fewer participants (\< 30%) experience hemolysis; * No participant experiences a drug-related serious adverse event; and * No participant requires a blood transfusion. Design: * This is an open-label, phase 2, dose-adjustment study. * The initial primaquine dose will be 0.40 mg/kg. Subsequent dose groups will be selected depending on the occurrence of adverse events in the previous dose group. Once the highest tolerable dose in G6PD-deficient (G6PDd) individuals is established, a control group of G6PD normal malaria-free men will be enrolled and evaluated under the highest tolerable dose of primaquine. Study Population: * Malian men aged 18-50 years without malaria infection. * The majority of study participants will be G6PDd. Study Size: This study will enroll 7 participants per dose group. If all dose groups are tested, this study will enroll approximately 28 participants. Study visit and duration: * Each participant will be followed for 28 days. * Participants will be evaluated for hemolysis and adverse events on Days 1-10, 14, and 28 following their assigned primaquine dose. Primary objective: To measure the change in hemoglobin among G6PD deficient west-African men following a single low-dose of primaquine not to exceed 0.75 mg/kg. Secondary objectives: 1. To measure the occurrence of adverse events, graded by severity, at each primaquine dose among G6PD deficient men 2. To measure the occurrence of markers of acute hemolytic anemia (AHA), at each primaquine dose among G6PD deficient men. AHA markers will include: * Absolute and fractional change in hemoglobin on day 7 vs. baseline * Urine color * Reticulocyte count * Bilirubin (both total and direct) * Methemoglobin concentration * Development of physical signs or symptoms of hemolytic anemia 3. To compare the change in hemoglobin, frequency and severity of adverse events, and occurrence of markers of AHA between G6PD deficient and non-deficient participants receiving the highest tolerable primaquine dose 4. To measure G6PD enzyme activity (semiquantitative testing, U / gHb) 5. To measure the pharmacokinetics of primaquine, carboxyprimaquine, and other metabolites according to plasma concentrations. 6. To genotype participant blood samples for cytochrome P450 2D6 (CYP2D6) single nucleotide polymorphisms (SNPs), to determine if potential hemolysis in G6PDd individuals is affected by CYP2D6 metabolizer status (e.g. weak metabolizers and/or intermediate metabolizers)
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
28
A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.
Malaria Research and Training Centre
Bamako, Mali
Primary outcome: the change in hemoglobin concentration from baseline levels following a single low-dose of primaquine not to exceed 0.75 mg/kg.
Time frame: Between day 0 and day 10.
To measure the occurrence of adverse events, graded by severity, at each primaquine dose among G6PD deficient men
Severity: 1. = mild 2. = moderate 3. = severe 4. = life threatening
Time frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28
To measure the occurrence of absolute and fractional change in hemoglobin concentration (g/dL) on day 7 vs. baseline at each primaquine dose among G6PD deficient men, in comparison with G6PD normal men
Time frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28
To measure the occurrence of reticulocytosis (by microscopic quantification of reticulocytes stained with brilliant cresyl blue / 1,000 RBCs) on each day of followup, at each primaquine dose, among G6PD deficient men, in comparison with G6PD normal men
Time frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28
To monitor methemoglobin levels (%) on each day of followup, at each primaquine dose among G6PD deficient men, in comparison with G6PD normal men
Use of a Masimo Rad-57 pulse oximeter that measures methemoglobin levels non-invasively, based on absorption of light through the fingertip.
Time frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28
To determine G6PD enzyme activity (semiquantitative testing, U/g Hb)
Semiquantitative testing will be performed on frozen blood samples to determine G6PD activity on day of enrolment
Time frame: Day 0
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Area Under Curve (AUC) for primaquine
Pharmacokinetic analysis of plasma concentration of primaquine at all sampled timepoints
Time frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration
Maximal concentration (Cmax) for primaquine
Pharmacokinetic analysis of plasma concentration of primaquine at all sampled timepoints
Time frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration
Area Under Curve (AUC) for carboxyprimaquine
Pharmacokinetic analysis of plasma concentration of carboxyprimaquine
Time frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration
Maximal concentration (Cmax) for carboxyprimaquine
Pharmacokinetic analysis of plasma concentration of carboxyprimaquine
Time frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration
Area Under Curve (AUC) for select minor metabolites of primaquine
Pharmacokinetic analysis of plasma concentration of metabolites of primaquine, exact metabolites to be determined by ongoing in vivo studies (including 5-hydroxyprimaquine)
Time frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration
Maximal concentration (Cmax) for select minor metabolites of primaquine
Pharmacokinetic analysis of plasma concentration of metabolites of primaquine, exact metabolites to be determined by ongoing in vivo studies (including 5-hydroxyprimaquine)
Time frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration
Cytochrome P450 (CYP) 2D6 genotyping
To determine whether a correlation between CYP 2D6 metabolism (weak metabolizer, intermediate metabolizer, normal metabolizer, ultrarapid metabolizer) and hemolysis exists.
Time frame: Day 0