Genetic Variability in CYP2D6 in U.S Active Duty Population

Walter Reed Army Institute of Research (WRAIR)

Status and phase: Completed; Phase 1

Conditions: Pharmacologic Action

Treatments: Drug: Primaquine

Study type: Interventional

Funder types: Other U.S. Federal agency

Identifiers

NCT02960568

D6.7_14_I_14_J9_837 (Other Grant/Funding Number)

WR2253

Details and patient eligibility

About

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.

Full 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.

Enrollment: 550 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Health Services Research

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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550 participants in 2 patient groups

Primaquine

Experimental group

Description:

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

Treatment:

Drug: Primaquine

No primaquine

No Intervention group

Description:

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