Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Abstract

e 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.

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

“…Our group has reported recently on the enantioselective pharmacologic, pharmacokinetic, and toxicologic properties for PQ in mice, dogs, and primates Saunders et al, 2014). These studies added to a body of literature that suggested important differences in these biologic activities for PQ enantiomers.…”

“…A more recent study in rhesus macaques (Macaca mulatta) has shown that treatment with (+)-PQ enantiomer caused greater methemoglobin toxicity than that seen for (2)-PQ. In combination with chloroquine, (2)-PQ was more effective in preventing P. cynomolgi relapse, a surrogate model for P. vixav relapse, compared with (+)-PQ (Saunders et al, 2014).…”

“…This method quantifies the [M+H] + ions of PQ, 4-methyl PQ (internal standard), and cPQ at m/z 260.1763, 274.1849, and 275.1396, respectively, in the positive ion mode with extractive ion monitoring (Avula et al, 2013). This method has been useful for investigating the enantioselective metabolism of PQ in rodent and primate animal models (Avula et al, 2011;Saunders et al, 2014). This method was further used to explore the pharmacokinetic and metabolic properties of the enantiomers of PQ in healthy human volunteers after administration of the racemic form of the drug.…”

Killing the hypnozoite – drug discovery approaches to prevent relapse inPlasmodium vivax

“…34 Whether the antihypnozoite effects of the active metabolite(s) can be separated from the haemolytic effects is an area of active investigation. 35,36 If CYP2D6 is necessary for metabolic activation, then efficacy (% cure) is subject to genetic polymorphisms. Individuals who are poor metabolizers may still be at risk for relapse.…”

Analytical Methods in the Quality Control of Scientific Publications Part V: The Fraud of Pseudoscientists Based on False Measurements and Method Development

“…In tablets, there are four different substances: two stereoisomers of primaquine and two stereoisomers of quinocide. These substances have different toxic, pathological and pharmacological effects on animals and humans [4]- [6]. In 2004, qualitative and quantitative information about primaquine tablets as mixtures of four individual substances and the influence of the contaminant quinocide on the overall toxicological effects of the drugs in these tablets was published [7].…”