Genetic Variability in CYP2D6 in U.S Active Duty Population

NCT ID: NCT02960568

Last Updated: 2021-10-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 550 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-08
• Study Completion Date: 2017-08-31

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.

Detailed Description

The investigator propose to enroll a group of active duty service members in order to determine individuals' 2D6 isoenzyme genotype, an enzyme belonging to the hepatic cytochrome P450 oxidase system. The 2D6 isoenzyme is a key enzyme involved in the metabolism of many drugs including the anti-malarial drug primaquine (PQ). By knowing the genotype, the investigator can then categorize each volunteer by CYP2D6 phenotype i.e., expected impact on drug metabolism. In order to further substantiate the relationship between CYP2D6 activity, inadequate metabolism and subsequent primaquine failure, the investigator proposes to assess the effect of 2D6 genetic polymorphisms on PQ metabolism by measuring the PQ pharmacokinetics (PK) over 24 hours following a single 30 mg oral dose in a subset of these Active Duty subjects.

Conditions

Pharmacologic Action

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: NONE

Study Groups

Primaquine

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

Group Type: EXPERIMENTAL

Primaquine

Intervention Type: DRUG

30 mg oral primaquine one time

No primaquine

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Primaquine

30 mg oral primaquine one time

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Walter Reed Army Institute of Research (WRAIR)

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Norman Waters, PhD

Role: STUDY_DIRECTOR

Walter Reed Army Institute of Research (WRAIR)

Locations

WRAIR

Silver Spring, Maryland, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31549155 (View on PubMed)

Other Identifiers

D6.7_14_I_14_J9_837

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

WR2253

Identifier Type: -

Identifier Source: org_study_id