Primaquine Enantiomers in G6PD Deficient Human Volunteers

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

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.

Study Overview

• Status: Unknown
• Conditions: G6PD Deficiency
• Intervention / Treatment: Drug: RPQ; Drug: SPQ; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Larry Walker, Ph.D.; Phone Number: 662-915-1005; Email: lwalker@olemiss.edu
• Study Contact Backup: Name: Kerri Harrison, RN; Phone Number: 662-915-2103; Email: laharri6@olemiss.edu

Study Locations

• United States
  • Mississippi
    • University, Mississippi, United States, 38677
      • Recruiting
      • University of Mississippi
      • Contact: Kerri Harrison, RN; Phone Number: 662-915-2103; Email: kaharri6@olemiss.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

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

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

Collaborators and Investigators

• Sponsor: University of Mississippi, Oxford
• Collaborators: University of Colorado, Denver; Southern Research Institute
• Investigators: Principal Investigator: Larry Walker, Ph.D., University of Mississippi Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Anticipated): September 1, 2021
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: August 28, 2019
• First Posted (Actual): August 29, 2019

Study Record Updates

• Last Update Posted (Actual): October 19, 2020
• Last Update Submitted That Met QC Criteria: October 14, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Malaria; Pharmacokinetics; Hemolysis; Primaquine; G6PD
• 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 3

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