Pharmacogenetics of antimalarial drugs: effect on metabolism and transport

Kerb, Reinhold; Fux, Richard; Mörike, Klaus; Kremsner, Peter G.; Gil, José Pedro; Gleiter, Christoph H.; Schwab, Matthias

doi:10.1016/s1473-3099(09)70320-2

Cited by 126 publications

(121 citation statements)

References 142 publications

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“…Indeed, PQ has been regarded as a drug without suspected pharmacogenetic variability in absorption, distribution, metabolism, or excretion (57). At present, there is not a plausible reason why PQ disposition might differ in Melanesian populations but, as with the longer-thanexpected elimination half-life of pyrimethamine in pregnant PNG women (19), this cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

Benjamin

Moore

Salman

et al. 2015

Antimicrob Agents Chemother

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The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC 0 -ؕ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

Benjamin

Moore

Salman

et al. 2015

Antimicrob Agents Chemother

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“…Several high-quality comprehensive reviews have been done elsewhere. 17,18 Table 3 lists the drugs and their potential relationships with various genes. This paper discusses ways to improve knowledge of genetic data in malaria-endemic regions and explores the issues that need to be addressed to make pharmacogenetic-guided drug policy a reality.…”

Section: Policy and Practicementioning

confidence: 99%

“…22 People with mutant genotypes of CYP2C8, CYP1A1 and CYP1B1 have been found to have immunogenic adverse reactions to amodiaquine. [23][24][25][26][27][28] Wide variations in the CYP2C8 genotype mean that individuals experience broad differences in the drug's efficacy and toxicity. Evidence suggests that decreased function of the CYP2C8 enzyme impairs metabolism of the drug and can form a toxic metabolite that causes hepatotoxicity and agranulocytosis.…”

Section: The Case Of Amodiaquinementioning

confidence: 99%

Can pharmacogenomics improve malaria drug policy?

Roederer

McLeod²,

Juliano

2011

Bull World Health Org

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“…Elimination of dihydroartemisinin is largely through the conversion to inactive glucuronide conjugates by UGT1A9 and UGT2B7 enzymes. 8 Therefore, the polymorphisms in CYP2A6 and UGT1A9 genes may be of clinical relevance to treatment response after artesunate-based combination therapy as a result of inadequate plasma concentrations of dihydroartemisinin in some patients. Patients with poor metabolic activity of CYP2A6 and/or CYP2B6 may have unusually low concentrations of the active metabolite dihydroartemisinin.…”

Section: Introductionmentioning

confidence: 99%

Preliminary Investigation of the Contribution of CYP2A6, CYP2B6, and UGT1A9 Polymorphisms on Artesunate-Mefloquine Treatment Response in Burmese Patients with Plasmodium falciparum Malaria

Phompradit¹,

Muhamad²,

Cheoymang³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. CYP2A6, CYP2B6, and UGT1A9 genetic polymorphisms and treatment response after a three-day course of artesunate-mefloquine was investigated in 71 Burmese patients with uncomplicated Plasmodium falciparum malaria. Results provide evidence for the possible link between CYP2A6 and CYP2B6 polymorphisms and plasma concentrations of artesunate/dihydroartemisinin and treatment response. In one patient who had the CYP2A6*1A/*4C genotype (decreased enzyme activity), plasma concentration of artesunate at one hour appeared to be higher, and the concentration of dihydroartemisinin was lower than for those carrying other genotypes (415 versus 320 ng/mL). The proportion of patients with adequate clinical and parasitologic response who had the CYP2B6*9/*9 genotype (mutant genotype) was significantly lower compared with those with late parasitologic failure (14.0% versus 19.0%). Confirmation through a larger study in various malaria-endemic areas is required before a definite conclusion on the role of genetic polymorphisms of these drugmetabolizing enzymes on treatment response after artesunate-based combination therapy can be made.

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Pharmacogenetics of antimalarial drugs: effect on metabolism and transport

Cited by 126 publications

References 142 publications

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

Can pharmacogenomics improve malaria drug policy?

Preliminary Investigation of the Contribution of CYP2A6, CYP2B6, and UGT1A9 Polymorphisms on Artesunate-Mefloquine Treatment Response in Burmese Patients with Plasmodium falciparum Malaria

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