Pharmacokinetics of primaquine in patients withP. Vivax malaria

Bhatia, S. C.; Saraph, Y. S.; Revankar, S. N.; Doshi, K. J.; Bharucha, E. D.; Desai, Nirmal D.; Vaidya, Akhil B.; Subrahmanyam, D. K. S.; Gupta, KL; Satoskar, R. S.

doi:10.1007/bf00606660

Cited by 37 publications

(31 citation statements)

References 10 publications

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“…Very high concentrations of cPQ, mostly (2)-cPQ, were still present at 24 hours Therefore, the half-life for cPQ enantiomers could not be computed from this experiment. However, the persistence of (2)-cPQ is consistent with earlier published studies on pharmacokinetics of racemic PQ Bhatia et al, 1986;Singhasivanon et al, 1991;Bangchang et al, 1994;Kim et al, 2004) and PQ in combination with chloroquine and artemisinin combinations (ACT) therapies Jittamala et al, 2015). The computed elimination half-lives of -PQ, (2)-PQ, and (+)-PQ were similar.…”

Section: Discussionsupporting

confidence: 88%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

et al. 2015

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Primaquine (PQ), a racemic drug, is the only treatment available for radical cure of relapsing Plasmodium vivax malaria and blocking transmission of P. falciparum malaria. Recent studies have shown differential pharmacologic and toxicologic profiles of individual PQ enantiomers in rodent, dog, and primate animal models. This study was conducted in six healthy adult human volunteers to determine the plasma pharmacokinetic profile of enantiomers of PQ and carboxyprimaquine (cPQ), the major plasma metabolite. The individuals were orally administered PQ diphosphate, equivalent to 45-mg base, 30 minutes after a normal breakfast. Blood samples were collected at different time intervals, and plasma samples were analyzed for enantiomers of PQ and cPQ. Plasma PQ concentrations were low and variable for both parent enantiomers and peaked around 2-4 hours. Peak (2)-(R)-PQ concentrations ranged from 121 ng/ml to 221 ng/ml, and peak (+)-(S)-PQ concentrations ranged from 168 ng/ml to 299 ng/ml. The cPQ concentrations were much higher and were surprisingly consistent from subject to subject. Essentially all the cPQ detected in plasma was (2)-cPQ. The peak concentrations of (2)-cPQ were observed at 8 hours (range: 1104-1756 ng/ml); however, very high concentrations were sustained through 24 hours. (+)-cPQ was two orders of magnitude lower than (2)-cPQ, and in a few subjects it was detected but only under the limit of quantification. In vitro studies with primary human hepatocytes also suggested more rapid metabolism of (2)-PQ compared with (+)-PQ. The results suggest more rapid metabolism of (2)-PQ to (2) cPQ compared with (+)-PQ. Alternatively, (+)-PQ or (+)-cPQ could be rapidly converted to another metabolite(s) or distributed to tissues. This is the first clinical report on enantioselective pharmacokinetic profiles of PQ and cPQ and supports further clinical evaluation of individual PQ enantiomers.

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Section: Discussionsupporting

confidence: 88%

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

et al. 2015

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“…Consistent with this, the increased V for (Ϫ)-PQ seen here could reflect greater hepatic uptake and explain not only the modestly increased antirelapse activity against liver-stage parasites but also a greater propensity for liver toxicity at high doses. Similar to what is seen in the primate model, peak cPQ serum levels are up to 10-fold higher than the parent drug 3 to 12 h postdose in humans (32). Thus, higher serum levels of (Ϫ)-cPQ in nonhuman primates may also reflect increased intrahepatic levels of the parent drug and lead to the hepatotoxicity seen here.…”

Section: Discussionsupporting

confidence: 77%

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

Saunders

Vanachayangkul

Im-Erbsin

et al. 2014

Antimicrob Agents Chemother

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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.

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“…Because it has an elimination half-life of 4 to 6 h (32), there is no significant PMQ accumulation with daily dosing. Therefore, the C max and area under the plasma concentration-time curve at the beginning and end of a 14-day course of daily PMQ doses are similar (1,33). This lack of time/dose-dependent kinetics improves the validity of extrapolation from single to multiple dosings in our simulations.…”

Section: Figmentioning

confidence: 79%

Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

Moore

Salman

Benjamin

et al. 2014

Antimicrob Agents Chemother

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f Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/ h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (C max ) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher C max for PMQ and CPMQ, respectively. All predicted median C max concentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group. P rimaquine (PMQ) is an 8-aminoquinoline drug used for primary (causal) and terminal malaria prophylaxis, radical cure of Plasmodium vivax and P. ovale, and as a gametocytocidal agent in P. falciparum infections (1-4). It remains the only FDA-approved drug for elimination of liver stages (hypnozoites and schizonts) of P. vivax and P. ovale (2,4,5). In many non-African tropical countries, such as Papua New Guinea (PNG), there is hyperendemic transmission of P. vivax (5-7). Children carry the burden of repeated P. vivax infections in this geoepidemiologic setting (5,8,9). Therefore, a safe and effective radical cure would benefit personal well-being, growth, and development and lessen the economic impact of the infection on the community (10).Primaquine is conventionally administered as a 14-day course for terminal prophylaxis and radical cure (2), but this regimen can be problematic due to poor compliance (1, 5). An abbreviated regimen would have advantages (11, 12) as long as it was safe and well tolerated. Pharmacokinetic studies of PMQ to date have been conducted only in adults (6). As the pharmacokinetic and pharmacodynamic profiles of antimalarial drugs can differ between adults and children (13), there is a need for a study of PMQ disposition in the pediatric age grou...

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Pharmacokinetics of primaquine in patients withP. Vivax malaria

Cited by 37 publications

References 10 publications

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

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

Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

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