Pharmacokinetics and pharmacodynamics of (+)-primaquine and (-)-primaquine enantiomers in rhesus macaques (Macaca mulatta)

Abstract

Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (-)-PQ enantiomer had higher clearance and apparent volume of distribution than did (+)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (+)-PQ greater than that seen for (-)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (-)-PQ at 4.5 mg/kg. (-)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (+)-PQ at 0.6 mg/kg/day relapsed. While (-)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (+) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.

FIG 1

Mirror image structures of primaquine enantiomers. (A) (+)-Primaquine; (B) (−)-primaquine. Enantiomers were prepared at the National Center for Natural Products Research, University of Mississippi.

FIG 2

Hepatotoxicity in healthy animals following 7 days of dosing with (+)/(−)-PQ or vehicle control (CTRL) at 4.5 mg/kg/day. (A) Alanine aminotransferase (ALT); (B) aspartate aminotransferase (AST); (C) total bilirubin.

FIG 3

Individual hematologic profiles. (A) Reticulocytes as percentages of total red blood cell counts following 7 days of oral dosing at 4.5 mg/kg/day in 6 healthy animals dosed with (+)-PQ or (−)-PQ and 1 vehicle control (CTRL). (B) Percent methemoglobin levels at 1.3, 3.0, and 4.5 mg/kg/day. Note that enantiomers were switched to opposite groups between 3.0 and 4.5 mg/kg/day.

FIG 4

Semi-log plots of means (± standard deviations [SD]) of concentration in plasma-time profiles of (−)-PQ/cPQ (A) and (+)-PQ/cPQ (B) enantiomers following 7 days of oral administration at 3.0 and 4.5 mg/kg/day.