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

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.

Study Overview

• Status: Completed
• Conditions: Malaria; Glucose 6 Phosphate Dehydrogenase Deficiency
• Intervention / Treatment: Drug: RPQ; Drug: SPQ; Drug: Primaquine Phosphate; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Mississippi
    • University, Mississippi, United States, 38677
      • University of Mississippi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Mississippi, Oxford
• Investigators: Principal Investigator: Larry Walker, Phd, University of Mississippi Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2018
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: May 14, 2018
• First Submitted That Met QC Criteria: April 30, 2019
• First Posted (Actual): May 1, 2019

Study Record Updates

• Last Update Posted (Actual): May 14, 2019
• Last Update Submitted That Met QC Criteria: May 13, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hemolysis; Primaquine
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Glucosephosphate Dehydrogenase Deficiency; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Primaquine
• Other Study ID Numbers: PQ Study 2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No