Metabolism and Pharmacokinetics of Primaquine Enantiomers in Human Volunteers, Study 1

NCT02898779 | Completed Phase 1 FDA Drug

• 1 other identifier: PQ Study 1
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria

Outcome Measures

Primary Outcomes (1)

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

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

  between 0-24 Hours

Secondary Outcomes (7)

• Area Under Curve (AUC) for primaquine up to 24 hours after the primaquine administration

  between 0-24 hours

• Maximum concentration (Cmax) for primaquine up to 24 hours after the primaquine administration

  between 0-24 hours

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

  between 0-24 hours

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

  between 0-24 hours

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

  between 0-24 hours

Study Arms (2)

Cohort 1 ( Primaquine Low Dose)

EXPERIMENTAL

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.

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

Cohort 2 (Primaquine High Dose)

EXPERIMENTAL

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.

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

Interventions

Primaquine, R-Primaquine, S-Primaquine, SR Primaquine DRUG

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.

Also known as: Primaquine

Cohort 1 ( Primaquine Low Dose); Cohort 2 (Primaquine High Dose)

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Mississippi, Oxford: lead

Study Sites (1)

University of Mississippi

Oxford, Mississippi, 38677, United States

Location

Related Publications (19)

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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.

  PMID: 18930565 RESULT

• 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 RESULT

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

• Babu L Tekwani, Ph.D

  University of Mississippi Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2016
• First Posted: September 13, 2016
• Study Start: May 1, 2017
• Primary Completion: March 1, 2018
• Study Completion: March 1, 2018
• Last Updated: May 15, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)