Genetic Variability in CYP2D6 in U.S Active Duty Population

Sponsor

Walter Reed Army Institute of Research (WRAIR) (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT02960568

Collaborator

(none)

550

Enrollment

Location

Arms

18.8

Actual Duration (Months)

29.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pharmacologic Action	Drug: Primaquine	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

550 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Health Services Research

Official Title:

Genetic Variability in the Cytochrome P-450 Isoenzyme 2D6 (CYP2D6) in an Active Duty U.S. Military Population and the Impact of CYP2D6 Phenotype on Primaquine Metabolism.

Actual Study Start Date :

Jan 8, 2016

Actual Primary Completion Date :

Jul 1, 2017

Actual Study Completion Date :

Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: Primaquine 30 mg oral primaquine one time
No Intervention: 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

Arm

Intervention/Treatment

Experimental: 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

Drug: Primaquine

30 mg oral primaquine one time

No Intervention: 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

Outcome Measures

Primary Outcome Measures

Description of CYP2D6 alleles in an active duty population [1 hour]
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.
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 Outcome Measures

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]
Develop pharmacokinetic curves of primaquine and its major metabolites with determinations of elimination half-life (t1/2), [1 month]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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