## Protocol Section
### Identification Module
**NCT ID:** NCT02898779

**Brief Title:** Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers, Study 1

**Official Title:** Development of Safer Drugs for Malaria in U.S. Troops, Civilian Personnel, and Travelers: Clinical Evaluation of Primaquine Enantiomer

#### Organization Study ID Info
**ID:** PQ Study 1
#### Organization
**Class:** OTHER
**Full Name:** University of Mississippi, Oxford
### Status Module
#### Completion Date
**Date:** 2018-03-01

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2018-05-15

**Type:** ACTUAL

**Last Update Submit Date:** 2018-05-14

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2018-03-01

**Type:** ACTUAL

#### Start Date
**Date:** 2017-05-01

**Type:** ACTUAL

**Status Verified Date:** 2018-05

#### Study First Post Date
**Date:** 2016-09-13
**Type:** ESTIMATED
**Study First Submit Date:** 2016-07-21
**Study First Submit QC Date:** 2016-09-07
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Mississippi, Oxford

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** To investigate the comparative tolerability, metabolism and pharmacokinetics of individual enantiomers of PQ in healthy human volunteers. The specific aim is the comparative evaluation of the metabolism, pharmacokinetic behavior, and tolerability of the isomers of PQ (RPQ and SPQ and the racemic mixture RSPQ) in normal healthy human volunteers.

**Detailed Description:** The primary objective of this project is to investigate the comparative tolerability, metabolism and pharmacokinetics of individual enantiomers of PQ in healthy human volunteers.

The overall approach is as follows: in 36 healthy volunteers with documented normal G6PD activity, we will administer a single oral dose of RPQ, SPQ, or RSPQ. At various times after dosing, we will draw blood samples, in which we will record the plasma levels of the parent drugs, along with plasma and urinary metabolites. The comparative pharmacokinetics, tolerability and hematological effects of these two enantiomers and the racemate will be assessed.

### Conditions Module

**Conditions:**

- Malaria

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

##### Masking Info

**Masking:** SINGLE

**Who Masked:**

- PARTICIPANT

**Primary Purpose:** BASIC_SCIENCE

#### Enrollment Info

**Count:** 36

**Type:** ACTUAL

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Interventions: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine A single center, prospective, cross-over, randomized phase 1 trial. Thirty-six participants, enrolled into a two cohort pharmacokinetic study evaluating two dose levels of primaquine isomers.

Cohort 1 (Low Dose Level)- single dose of 15 mg of S-Primaquine and 15 mg of R-Primaquine compared to 30 mg RS-Primaquine over 24 hours. Participants will cross-over after a one week wash-out period.

**Intervention Names:**

- Drug: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine

**Label:** Cohort 1 ( Primaquine Low Dose)

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Interventions: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine A single center, prospective, cross-over, randomized phase 1 trial. Thirty-six participants, enrolled into a two cohort pharmacokinetic study evaluating two dose levels of primaquine isomers.

Cohort 2 (High Dose Level)-single dose of 22.5 mg of S-Primaquine and 22.5 mg of R-Primaquine compared to 45 mg RS-Primaquine over 24 hours. Participants will cross-over among the treatment arms following a one week wash-out period between each.

**Intervention Names:**

- Drug: Primaquine, R-Primaquine, S-Primaquine, SR Primaquine

**Label:** Cohort 2 (Primaquine High Dose)

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Cohort 1 ( Primaquine Low Dose)

- Cohort 2 (Primaquine High Dose)

**Description:** Cohort 1: Eighteen individuals (6 per group) Cohort 2: Eighteen individuals (6 per group)

Group 1-15 mg of S-Primaquine followed by one-week washout, 15 mg of R-Primaquine followed by one week washout, and 30 mg of RS-Primaquine.

Group 2- 15 mg of R-Primaquine followed by one-week washout, 30 mg of RSPQ followed by one week washout, and 15 mg of SPQ.

Group 3- 30 mg of RS-Primaquine followed by one week washout,15 mg of SPQ followed by a one week washout, and 15 mg of RPQ.

**Name:** Primaquine, R-Primaquine, S-Primaquine, SR Primaquine

**Other Names:**

- Primaquine

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers

**Measure:** Primary outcome: Plasma concentration of parent primaquine and carboyprimaquine following a single dose treatment with primaquine (racemate or enantiomers) not to exceed 45 mg

**Time Frame:** between 0-24 Hours

#### Secondary Outcomes

**Description:** This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers

**Measure:** Area Under Curve (AUC) for primaquine up to 24 hours after the primaquine administration

**Time Frame:** between 0-24 hours

**Description:** This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers

**Measure:** Maximum concentration (Cmax) for primaquine up to 24 hours after the primaquine administration

**Time Frame:** between 0-24 hours

**Description:** This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers

**Measure:** Area Under Curve (AUC) for carboxyprimaquine, the major plasma metabolite of primaquine, up to 24 hours after primaquine administration

**Time Frame:** between 0-24 hours

**Description:** This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers

**Measure:** Maximum concentration of carboxyprimaquine, the major plasma metabolite of primaquine, up to 24 hours after primaquine administration

**Time Frame:** between 0-24 hours

**Description:** This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers. The exact nature of these metabolites will be determined from previous animal and human studies

**Measure:** Maximum concentration of selected metabolites primaquine (other than carboxyprimaquine) up to 24 hours after primaquine administration

**Time Frame:** between 0-24 hours

**Description:** To monitor hemoglobin and methemoglobin levels in normal human volunteers treated with single dose of primaquine not to exceed 45 mg

**Measure:** hemoglobin and methemoglobin levels in the blood after administration of primaquine

**Time Frame:** 0-72 hours

**Description:** To determine correlation between metabolism of primaquine and CYP 2D6 genotype

**Measure:** Genotyping of Cytochrome P-450 (CYP)

**Time Frame:** day 0

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Adults (18-60 years of age)
* Informed consent
* Healthy

Exclusion Criteria:

* Known history of liver, kidney or hematological disease;
* known history of cardiac disease, arrhythmia, QT prolongation;
* Autoimmune disorder;
* Report of an active infection;
* Evidence of G6PD deficiency

**Healthy Volunteers:** True

**Maximum Age:** 60 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Oxford

**Country:** United States

**Facility:** University of Mississippi

**State:** Mississippi

**Zip:** 38677

#### Overall Officials

**Official 1:**

**Affiliation:** University of Mississippi Medical Center

**Name:** Babu L Tekwani, Ph.D

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** Avula B, Tekwani BL, Chaurasiya ND, Nanayakkara NP, Wang YH, Khan SI, Adelli VR, Sahu R, Elsohly MA, McChesney JD, Khan IA, Walker LA. Profiling primaquine metabolites in primary human hepatocytes using UHPLC-QTOF-MS with 13C stable isotope labeling. J Mass Spectrom. 2013 Feb;48(2):276-85. doi: 10.1002/jms.3122.

**PMID:** 23378100

**Citation:** Avula B, Khan SI, Tekwani BL, Nanayakkara NP, McChesney JD, Walker LA, Khan IA. Analysis of primaquine and its metabolite carboxyprimaquine in biological samples: enantiomeric separation, method validation and quantification. Biomed Chromatogr. 2011 Sep;25(9):1010-7. doi: 10.1002/bmc.1557. Epub 2010 Nov 5.

**PMID:** 21058417

**Citation:** Baker JK, McChesney JD. Differential metabolism of the enantiomers of primaquine. J Pharm Sci. 1988 May;77(5):380-2. doi: 10.1002/jps.2600770503.

**PMID:** 3411455

**Citation:** Lu H. Stereoselectivity in drug metabolism. Expert Opin Drug Metab Toxicol. 2007 Apr;3(2):149-58. doi: 10.1517/17425255.3.2.149.

**PMID:** 17428147

**Citation:** Fasinu PS, Tekwani BL, Nanayakkara NP, Avula B, Herath HM, Wang YH, Adelli VR, Elsohly MA, Khan SI, Khan IA, Pybus BS, Marcsisin SR, Reichard GA, McChesney JD, Walker LA. Enantioselective metabolism of primaquine by human CYP2D6. Malar J. 2014 Dec 17;13:507. doi: 10.1186/1475-2875-13-507.

**PMID:** 25518709

**Citation:** Fasinu PS, Avula B, Tekwani BL, Nanayakkara NP, Wang YH, Bandara Herath HM, McChesney JD, Reichard GA, Marcsisin SR, Elsohly MA, Khan SI, Khan IA, Walker LA. Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes. Malar J. 2016 Apr 19;15:224. doi: 10.1186/s12936-016-1270-1.

**PMID:** 27093859

**Citation:** Graves PM, Gelband H, Garner P. Primaquine or other 8-aminoquinoline for reducing Plasmodium falciparum transmission. Cochrane Database Syst Rev. 2015 Feb 19;(2):CD008152. doi: 10.1002/14651858.CD008152.pub4.

**PMID:** 25693791

**Citation:** Jin X, Pybus BS, Marcsisin R, Logan T, Luong TL, Sousa J, Matlock N, Collazo V, Asher C, Carroll D, Olmeda R, Walker LA, Kozar MP, Melendez V. An LC-MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model. Eur J Drug Metab Pharmacokinet. 2014 Jun;39(2):139-46. doi: 10.1007/s13318-013-0139-8.

**PMID:** 23797843

**Citation:** Mihaly GW, Ward SA, Edwards G, Orme ML, Breckenridge AM. Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite. Br J Clin Pharmacol. 1984 Apr;17(4):441-6. doi: 10.1111/j.1365-2125.1984.tb02369.x.

**PMID:** 6721990

**Citation:** Nanayakkara NP, Ager AL Jr, Bartlett MS, Yardley V, Croft SL, Khan IA, McChesney JD, Walker LA. Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate. Antimicrob Agents Chemother. 2008 Jun;52(6):2130-7. doi: 10.1128/AAC.00645-07. Epub 2008 Mar 31.

**PMID:** 18378716

**Citation:** Nanayakkara NP, Tekwani BL, Herath HM, Sahu R, Gettayacamin M, Tungtaeng A, van Gessel Y, Baresel P, Wickham KS, Bartlett MS, Fronczek FR, Melendez V, Ohrt C, Reichard GA, McChesney JD, Rochford R, Walker LA. Scalable preparation and differential pharmacologic and toxicologic profiles of primaquine enantiomers. Antimicrob Agents Chemother. 2014 Aug;58(8):4737-44. doi: 10.1128/AAC.02674-13. Epub 2014 Jun 9.

**PMID:** 24913163

**Citation:** Potter BM, Xie LH, Vuong C, Zhang J, Zhang P, Duan D, Luong TL, Bandara Herath HM, Dhammika Nanayakkara NP, Tekwani BL, Walker LA, Nolan CK, Sciotti RJ, Zottig VE, Smith PL, Paris RM, Read LT, Li Q, Pybus BS, Sousa JC, Reichard GA, Marcsisin SR. Differential CYP 2D6 metabolism alters primaquine pharmacokinetics. Antimicrob Agents Chemother. 2015 Apr;59(4):2380-7. doi: 10.1128/AAC.00015-15. Epub 2015 Feb 2.

**PMID:** 25645856

**Citation:** Pybus BS, Marcsisin SR, Jin X, Deye G, Sousa JC, Li Q, Caridha D, Zeng Q, Reichard GA, Ockenhouse C, Bennett J, Walker LA, Ohrt C, Melendez V. The metabolism of primaquine to its active metabolite is dependent on CYP 2D6. Malar J. 2013 Jun 20;12:212. doi: 10.1186/1475-2875-12-212.

**PMID:** 23782898

**Citation:** Saunders D, Vanachayangkul P, Imerbsin R, Khemawoot P, Siripokasupkul R, Tekwani BL, Sampath A, Nanayakkara NP, Ohrt C, Lanteri C, Gettyacamin M, Teja-Isavadharm P, Walker L. Pharmacokinetics and pharmacodynamics of (+)-primaquine and (-)-primaquine enantiomers in rhesus macaques (Macaca mulatta). Antimicrob Agents Chemother. 2014 Dec;58(12):7283-91. doi: 10.1128/AAC.02576-13. Epub 2014 Sep 29.

**PMID:** 25267666

**Citation:** Schmidt LH, Alexander S, Allen L, Rasco J. Comparison of the curative antimalarial activities and toxicities of primaquine and its d and l isomers. Antimicrob Agents Chemother. 1977 Jul;12(1):51-60. doi: 10.1128/AAC.12.1.51.

**PMID:** 407841

**Citation:** Tekwani BL, Walker LA. 8-Aminoquinolines: future role as antiprotozoal drugs. Curr Opin Infect Dis. 2006 Dec;19(6):623-31. doi: 10.1097/QCO.0b013e328010b848.

**PMID:** 17075340

**Citation:** Tekwani BL, Avula B, Sahu R, Chaurasiya ND, Khan SI, Jain S, Fasinu PS, Herath HM, Stanford D, Nanayakkara NP, McChesney JD, Yates TW, ElSohly MA, Khan IA, Walker LA. Enantioselective pharmacokinetics of primaquine in healthy human volunteers. Drug Metab Dispos. 2015 Apr;43(4):571-7. doi: 10.1124/dmd.114.061127. Epub 2015 Jan 30.

**PMID:** 25637634

**Citation:** Vale N, Moreira R, Gomes P. Primaquine revisited six decades after its discovery. Eur J Med Chem. 2009 Mar;44(3):937-53. doi: 10.1016/j.ejmech.2008.08.011. Epub 2008 Sep 11.

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**Citation:** Vasquez-Vivar J, Augusto O. Hydroxylated metabolites of the antimalarial drug primaquine. Oxidation and redox cycling. J Biol Chem. 1992 Apr 5;267(10):6848-54.

**PMID:** 1313024

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000011528

- Term: Protozoan Infections

- ID: D000010272

- Term: Parasitic Diseases

- ID: D000007239

- Term: Infections

- ID: D000096724

- Term: Mosquito-Borne Diseases

- ID: D000079426

- Term: Vector Borne Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M11280

- Name: Malaria

- Relevance: HIGH

- As Found: Malaria

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14388

- Name: Protozoan Infections

- Relevance: LOW

- As Found: Unknown

- ID: M13185

- Name: Parasitic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M3255

- Name: Mosquito-Borne Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M2054

- Name: Vector Borne Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T3571

- Name: Malaria

- Relevance: HIGH

- As Found: Malaria

### Condition Browse Module - Meshes

- ID: D000008288

- Term: Malaria

### Intervention Browse Module - Ancestors

- ID: D000000962

- Term: Antimalarials

- ID: D000000981

- Term: Antiprotozoal Agents

- ID: D000000977

- Term: Antiparasitic Agents

- ID: D000000890

- Term: Anti-Infective Agents

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M14192

- Name: Primaquine

- Relevance: HIGH

- As Found: Adequate

- ID: M4280

- Name: Antimalarials

- Relevance: LOW

- As Found: Unknown

- ID: M4298

- Name: Antiprotozoal Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4294

- Name: Antiparasitic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4214

- Name: Anti-Infective Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000011319

- Term: Primaquine

### Misc Info Module

- Version Holder: 2024-05-24
