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

Malaria Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02898779
• Other study ID #: PQ Study 1
• Status: Completed
• Phase: Phase 1
• Start date: May 1, 2017
• Est. completion date: March 1, 2018

Study information

• Verified date: May 2018
• Source: University of Mississippi, Oxford
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: March 1, 2018
• Est. primary completion date: March 1, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Malaria

Intervention

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

Locations

Country	Name	City	State
United States	University of Mississippi	Oxford	Mississippi

Sponsors (1)

Lead Sponsor	Collaborator
University of Mississippi, Oxford

Country where clinical trial is conducted

United States, 

References & Publications (19)

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;2 — View 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 Ma — View Citation

Baker JK, McChesney JD. Differential metabolism of the enantiomers of primaquine. J Pharm Sci. 1988 May;77(5):380-2. — View 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. Mala — View 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;13:5 — View 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. Review. Update in: Cochrane Database Syst Rev. — View 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 — View Citation

Lu H. Stereoselectivity in drug metabolism. Expert Opin Drug Metab Toxicol. 2007 Apr;3(2):149-58. Review. — View 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. — View 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-dichloroph — View 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 pharmaco — View 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. Different — View 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: — View 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 enant — View 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. — View 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 — View Citation

Tekwani BL, Walker LA. 8-Aminoquinolines: future role as antiprotozoal drugs. Curr Opin Infect Dis. 2006 Dec;19(6):623-31. Review. — View 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. Review. — View Citation

Vásquez-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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Area Under Curve (AUC) for primaquine up to 24 hours after the primaquine administration	This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers	between 0-24 hours
Secondary	Maximum concentration (Cmax) for primaquine up to 24 hours after the primaquine administration	This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers	between 0-24 hours
Secondary	Area Under Curve (AUC) for carboxyprimaquine, the major plasma metabolite of primaquine, up to 24 hours after primaquine administration	This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers	between 0-24 hours
Secondary	Maximum concentration of carboxyprimaquine, the major plasma metabolite of primaquine, up to 24 hours after primaquine administration	This study would provide information on differential pharmacokinetics and metabolism of enantiomers of primaquine in normal human volunteers	between 0-24 hours
Secondary	Maximum concentration of selected metabolites primaquine (other than carboxyprimaquine) up to 24 hours after primaquine administration	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	between 0-24 hours
Secondary	hemoglobin and methemoglobin levels in the blood after administration of primaquine	To monitor hemoglobin and methemoglobin levels in normal human volunteers treated with single dose of primaquine not to exceed 45 mg	0-72 hours
Secondary	Genotyping of Cytochrome P-450 (CYP)	To determine correlation between metabolism of primaquine and CYP 2D6 genotype	day 0