Primaquine Enantiomers in G6PD Deficient Human Volunteers

Overview

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.

Full Title of Study: “Metabolism and Pharmacokinetics of Primaquine Enantiomers in G6PD Deficient Human Volunteers Receiving a Five Day Dose Regimen”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Basic Science
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 1, 2020

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.

Interventions

  • Drug: RPQ
    • The study will compare the individual enantiomers of Primaquine -R-(-)-PQ, S-(+)-PQ, and Placebo.
  • Drug: SPQ
    • The study will compare the individual enantiomers of Primaquine -R-(-)-PQ, S-(+)-PQ, and Placebo.
  • Drug: Placebo
    • The study will compare the individual enantiomers of Primaquine -R-(-)-PQ, S-(+)-PQ, and Placebo.

Arms, Groups and Cohorts

  • 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.
  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Change in Methemoglobin concentration in blood from baseline
    • Time Frame: Days 0, 3, 5
    • Change in Methemoglobin concentration in blood from baseline (% hemoglobin)

Secondary Measures

  • Primaquine Plasma Concentration, ng/mL
    • Time Frame: Days 0, 3, 5
    • Plasma concentrations of parent drug
  • Carboxy-Primaquine Plasma Contration, ng/mL
    • Time Frame: Days 0, 3, 5
    • Plasma concentrations of carboxy-primaquine metabolite
  • Primaquine N-carbamoyl-glucuronide Plasma contration, ng/mL
    • Time Frame: Days 0, 3, 5
    • Plasma concentrations of Primaquine N-carbamoyl-glucuronide metabolite
  • Primaquine Orthoquinone Plasma concentration, ng/mL
    • Time Frame: Days 0, 3, 5
    • Plasma concentrations of Primaquine Orthoquinone metabolite
  • Change in Hematocrit (%) compared to baseline
    • Time Frame: Days 0, 3, 5
    • Change in Hematocrit (%) compared to baseline
  • Change in Hemoglobin (g/dL) compared to baseline
    • Time Frame: Days 0, 3, 5
    • Change in Hemoglobin (g/dL) compared to baseline
  • Change is AST (U/L) compared to baseline
    • Time Frame: Days 0, 3, 5
    • Change is AST (U/L) compared to baseline; used to monitor liver function
  • Change in ALT (U/L) compared to baseline
    • Time Frame: Days 0, 3, 5
    • Change in ALT (U/L) compared to baseline; used to monitor liver function
  • Change in total Bilirubin (mg/dL) compared to baseline
    • Time Frame: Days 0, 3, 5
    • Change in total Bilirubin (mg/dL) compared to baseline; used to monitor liver function and red cell integrity

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Mississippi, Oxford
  • Collaborator
    • University of Colorado, Denver
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Larry Walker, Ph.D., Principal Investigator, University of Mississippi Medical Center
  • Overall Contact(s)
    • Larry Walker, Ph.D., 662-915-1005, lwalker@olemiss.edu

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