Genetic Variability in CYP2D6 in U.S Active Duty Population

NCT02960568 | Completed Phase 1

• 2 other identifiers: WR2253D6.7_14_I_14_J9_837
• Study Type: interventional
• Target: 550
• Locations: 1 country
• Sites: 1

Brief Summary

The investigator proposes to 2D6 (Cytochrome P-450 Isoenzyme 2D6) genotype and phenotype a group of active duty service members and assess the effects on primaquine metabolism.

Conditions

Pharmacologic Action

Keywords

primaquine; metabolism; malaria; hypnozoite; vivax; CYP2D6; active duty personnel

Outcome Measures

Primary Outcomes (3)

• Description of CYP2D6 alleles in an active duty population

  Genotyping of CYP2D6 alleles will be analyzed by a multiplexed cytometric bead array assay, Luminex xTAG® CYP2D6 Kit v3 (Austin, TX) which allows for detection of the 16 major alleles of 2D6 in the United States: 1,2,3,4,5,6,7,8,9,10,11,15, 17,29, 35,41. Subjects will then be categorized by CYP2D6 phenotype according to standard definitions of enzyme metabolic activity of specific 2D6 alleles using the published activity score model: AS Model A (1): "poor" (PM), "intermediate" (IM), "extensive" (EM) or "ultra (UM)" enzyme activity compared to the general population. Alleles known to have no activity are scored "0", intermediate activity alleles are scored as 0.5, while alleles with normal activity are scored as 1. Scores of both alleles making up the genotype are then added together to give the AS-Model A score and range from 0 to 2, with 0 indicating little or no CYP2D6 activity and 1 or 2 indicating normal levels of CYP2D6. Data will be descriptively analyzed.

  1 hour

• Measure concentrations of plasma primaquine and its major metabolites.

  24 hours

• Develop pharmacokinetic curves of primaquine and its major metabolites with determinations of Area under the curve (AUC)

  1 month

Other Outcomes (4)

• Develop pharmacokinetic curves of primaquine and its major metabolites with determinations of maximum concentration (Cmax)

  1 month

• Develop pharmacokinetic curves of primaquine and its major metabolites with determinations of time to reach maximum concentration (Tmax)

  1 month

• Develop pharmacokinetic curves of primaquine and its major metabolites with determinations of rate constant (kelim)

  1 month

Study Arms (2)

Primaquine

EXPERIMENTAL

Poor and Intermediate Metabolizers will receive 30 mg oral primaquine (PQ) and have peripheral blood draws over a 24-hour period to measure PQ pharmacokinetics

Drug: Primaquine

No primaquine

NO INTERVENTION

Extensive and Ultra Metabolizers will not be eligible for the pharmacokinetic portion of the study and participation will be complete after receiving genotype information

Interventions

Primaquine DRUG

30 mg oral primaquine one time

Primaquine

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Active duty Service member, (male or female) 18 to 60 years of age (inclusive) at the time of enrollment
• Written informed consent for phase 1 must be obtained
• Written informed consent for phase 2 must be obtained from the subject before the screening procedures
• Free of significant health problems as established by medical history, laboratory and clinical examination before entering the study
• If the subject is female, she must be of non-childbearing potential (either surgically sterilized or one year post-menopausal) or, if of childbearing potential, she must be capable of preventing pregnancy, have a negative pregnancy test at the time of the administration of primaquine , and must agree to continue such precautions until 48 hours after primaquine administration.
• Normal (non-deficient) G6PD (glucose-6-phosphate dehydrogenase) phenotype (range: 4.6 to 13.5 units/gm hemoglobin)
• Subjects must obtain approval from his or her supervisor per Walter Reed Army Institute of Research (WRAIR) Policy 06-15 in order to be participate in the PQ PK portion of phase 2

You may not qualify if:

• Use of any investigational or non-registered drug within 30 days preceding the primaquine dosing.
• Pregnant (positive urine β-HCG) or nursing at screening or plans to become pregnant or nurse from the time of enrollment until 48 hours after primaquine dosing.
• Allergy to primaquine
• Use of medications known to cause drug interactions with primaquine or CYP2D6
• Acute or chronic, clinically significant, pulmonary, cardiovascular, hepatic, neurologic, or renal functional abnormality, as determined by history, physical examination, and laboratory evaluation
• History of hemolytic anemia
• Any abnormal baseline laboratory screening tests listed below (normal values are defined by the current Quest Diagnostics reference guide on file in the CTC):
• ALT (alanine aminotransferase)above normal range
• Glomerular filtration rate (GFR) below normal range for the subject's ethnicity
• Hemoglobin below normal range
• Hepatomegaly, right upper quadrant abdominal pain or tenderness
• Suspected or known current alcohol abuse as determined from the medical history or by physical examination
• Use of any drugs that may cause hemolytic anemia and/or bone marrow suppression such as quinacrine, dapsone, rifampin, colchicine, ribavirin, penicillamine and sulfonamides.
• Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study

Sponsors & Collaborators

• Walter Reed Army Institute of Research (WRAIR): lead

Study Sites (1)

WRAIR

Silver Spring, Maryland, 20910, United States

Location

Related Publications (1)

• Spring MD, Sousa JC, Li Q, Darko CA, Morrison MN, Marcsisin SR, Mills KT, Potter BM, Paolino KM, Twomey PS, Moon JE, Tosh DM, Cicatelli SB, Froude JW, Pybus BS, Oliver TG, McCarthy WF, Waters NC, Smith PL, Reichard GA, Bennett JW. Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population. J Infect Dis. 2019 Oct 22;220(11):1761-1770. doi: 10.1093/infdis/jiz386.

  PMID: 31549155 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Primaquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Norman Waters, PhD

  Walter Reed Army Institute of Research (WRAIR)

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2016
• First Posted: November 9, 2016
• Study Start: January 8, 2016
• Primary Completion: July 1, 2017
• Study Completion: August 1, 2017
• Last Updated: October 20, 2021

Record last verified: 2021-10

Locations

US (1)