Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers

Khan, Washim; Wang, Yan-Hong; Chaurasiya, Narayan D.; Nanayakkara, N. P. Dhammika; Herath, H. M. T. Bandara; Harrison, Kerri A.; Dale, Gray; Stanford, Donald A.; Dahl, Eric; McChesney, James D.; Gul, Waseem; ElSohly, Mahmoud A.; Khan, Shabana I.; Fasinu, Pius S.; Khan, Ikhlas A.; Tekwani, Babu L.; Walker, Larry

doi:10.1016/j.dmpk.2022.100463

Cited by 3 publications

(14 citation statements)

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“…During daily PQ administration for 7 days (days 0–6), blood samples were taken on day zero pre-dose, on day three pre-dose and at 1 h post-dose, on day five pre-dose and at 1 h post-dose, and on day seven, 24 h after the last dose. The plasma concentrations of PQ on days 3 and 5 were very low at pre-dose, consistent with our prior study ( Khan et al, 2022a ) and those of others ( Mihaly et al, 1984 ), and increased 1 h after oral administration ( Figure 3 ). Two major metabolites of PQ ( Figure 3A ), cPQ ( Figure 3B ) and PQ-N-CG ( Figure 3C ), were measured in plasma at these time intervals.…”

Section: Resultssupporting

confidence: 91%

“…When the racemic mixture RSPQ was administered, both PQ and cPQ were high, reflecting the contribution of each enantiomer. Although the dose of RSPQ was the sum of the individual enantiomers, levels of PQ and cPQ were not doubled, presumably reflecting at least in part, a higher apparent volume of distribution (Vd) for RPQ as compared to SPQ in mice ( Fasinu et al, 2022 ), monkeys ( Saunders et al, 2014 ) and humans ( Khan et al, 2022a ), and also an expected much lower Vd for cPQ as compared to PQ ( Baker et al, 1984 ).…”

Section: Resultsmentioning

confidence: 99%

“…Clinical pharmacokinetic studies in G6PDn subjects were single-blinded, placebo-controlled crossover studies conducted at the National Center for Natural Products Research, University of Mississippi, United States of America. Dose selection was based on the clear safety and tolerability from our previous single dose study using SPQ, RPQ, and RSPQ ( Khan et al, 2022a ) and also from previous clinical studies with racemic PQ ( Bancone and Chu, 2021 ). The study in G6PDn volunteers consisted of four arms.…”

Section: Methodsmentioning

confidence: 99%

“…All the stored plasma and RBCs samples were thawed in ice and processed to quantify analytes. PQ, cPQ, and PQ-N-CG by a validated ultra-high performance liquid chromatography coupled with Xevo G2-S QToF mass spectrometer (UHPLC-MSMS) (Waters Corp., Milford, MA, United States) ( Khan et al, 2022a ). As the levels of POQ and cPOQ in plasma were very low, and QToF was not sensitive enough, these two analytes were quantified using Xevo TQ-S triple quadrupole mass spectrometer (UHPLC-TQ-MS, Waters Corp., Milford, MA, United States).…”

Section: Methodsmentioning

confidence: 99%

“…cPQ was the predominant plasma metabolite with the ( R )-enantiomer, many fold higher than the parent drug, but PQ-N-CG was not detected. In contrast, for the ( S )-enantiomer, PQ-N-CG was the major plasma metabolite, while very low levels of cPQ were seen ( Khan et al, 2022a ). Both enantiomers and the racemate were well tolerated at single doses of 22.5 mg and 45 mg for enantiomers and racemate, respectively.…”

Section: Introductionmentioning

confidence: 91%

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Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

et al. 2023

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Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

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Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

et al. 2023

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Quantitative analysis of primaquine and its metabolites in human urine using liquid chromatography coupled with tandem mass spectrometry

Khan

Wang

Nanayakkara

et al. 2022

Journal of Chromatography B

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A nanochitosan-D-galactose formulation increases the accumulation of primaquine in the liver

Gomes,

Ribeiro,

Sanches

et al. 2024

Antimicrob Agents Chemother

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Primaquine is the mainstream antimalarial drug to prevent Plasmodium vivax relapses. However, this drug can induce hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Nanostructure formulations of primaquine loaded with D-galactose were used as a strategy to target the drug to the liver and decrease the hemolytic risks. Nanoemulsion (NE-Pq) and nanochitosan (NQ-Pq) formulations of primaquine diphosphate containing D-galactose were prepared and characterized by their physicochemistry properties. Pharmacokinetic and biodistribution studies were conducted using Swiss Webster mice. A single dose of 10 mg/kg of each nanoformulation or free primaquine solution was administered by gavage to the animals, which were killed at 0.5, 1, 2, 4, 8, and 24 hours. Blood samples and tissues were collected, processed, and analyzed by high-performance liquid chromatography. The nanoformulation showed sizes around 200 nm (NE-Pq) and 400 nm (NQ-Pq) and physicochemical stability for over 30 days. Free primaquine solution achieved higher primaquine Cmax in the liver than NE-Pq or NQ-Pq at 0.5 hours. However, the half-life and mean residence time (MRT) of primaquine in the liver were three times higher with the NQ-Pq formulation than with free primaquine, and the volume distribution was four times higher. Conversely, primaquine’s half-life, MRT, and volume distribution in the plasma were lower for NQ-Pq than for free primaquine. NE-Pq, on the other hand, accumulated more in the lungs but not in the liver. Galactose-coated primaquine nanochitosan formulation showed increased drug targeting to the liver compared to free primaquine and may represent a promising strategy for a more efficient and safer radical cure for vivax malaria.

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Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers

Cited by 3 publications

References 30 publications

Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

Quantitative analysis of primaquine and its metabolites in human urine using liquid chromatography coupled with tandem mass spectrometry

A nanochitosan-D-galactose formulation increases the accumulation of primaquine in the liver

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