Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

Tärning, Joel; Kloprogge, Frank; Piola, Patrice; Dhorda, Mehul; Muwanga, Sulaiman; Turyakira, Eleanor; Nuengchamnong, Nitra; Nosten, François; Day, Nicholas P. J.; White, Nicholas J.; Guérin, Philippe J.; Lindegårdh, Niklas

doi:10.1186/1475-2875-11-293

Cited by 38 publications

(40 citation statements)

References 51 publications

(66 reference statements)

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“…The roles of different covariates that could influence AL bioavailability, distribution, and clearance in the two groups were carefully analyzed. This study differs from previous reports of population pharmacokinetics of AM and LF during pregnancy (16,18,19) by having a comparative group of nonpregnant women with malaria from the same population with relatively similar characteristics.…”

Section: Discussionmentioning

confidence: 41%

“…Several PK studies on artemether (AM) and lumefantrine (LF) and their respective metabolites, dihydroartemisinin (DHA) and debutyl-lumefantrine (DLF), have demonstrated low concentrations of these drugs in plasma in pregnant women compared to nonpregnant adults. However, most of these studies included healthy male adult volunteers as a comparative group rather than female malaria patients (16)(17)(18)(19). Because of various determinants of PK and therapeutic outcome, it is essential to have a comparative population of nonpregnant women of the same study area with the same disease.…”

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confidence: 99%

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Population Pharmacokinetics and Clinical Response for Artemether-Lumefantrine in Pregnant and Nonpregnant Women with Uncomplicated Plasmodium falciparum Malaria in Tanzania

Mosha

Guidi

Mwingira

et al. 2014

Antimicrob Agents Chemother

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e Artemether-lumefantrine (AL) is the first-line treatment for uncomplicated malaria in the second and third trimesters of pregnancy. Its efficacy during pregnancy has recently been challenged due to altered pharmacokinetic (PK) properties in this vulnerable group. The aim of this study was to determine the PK profile of AL in pregnant and nonpregnant women and assess their therapeutic outcome. Thirty-three pregnant women and 22 nonpregnant women with malaria were treated with AL (80/480 mg) twice daily for 3 days. All patients provided five venous plasma samples for drug quantification at random times over 7 days. Inter-and intraindividual variability was assessed, and the effects of covariates were quantified using a nonlinear mixed-effects modeling approach (NONMEM). A one-compartment model with first-order absorption and elimination with linear metabolism from drug to metabolite fitted the data best for both arthemether (AM) and lumefantrine (LF) and their metabolites. Pregnancy status and diarrhea showed a significant influence on LF PK. The relative bioavailability of lumefantrine and its metabolism rate into desmethyl-lumefantrine were, respectively, 34% lower and 78% higher in pregnant women than in nonpregnant patients. The overall PCR-uncorrected treatment failure rates were 18% in pregnant women and 5% in nonpregnant women (odds ratio [OR] ‫؍‬ 4.04; P value of 0.22). A high median day 7 lumefantrine concentration was significantly associated with adequate clinical and parasitological response (P ‫؍‬ 0.03). The observed reduction in the relative bioavailability of lumefantrine in pregnant women may explain the higher treatment failure in this group, mostly due to lower posttreatment prophylaxis. Hence, a modified treatment regimen of malaria in pregnancy should be considered.

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Section: Discussionmentioning

confidence: 41%

mentioning

confidence: 99%

Population Pharmacokinetics and Clinical Response for Artemether-Lumefantrine in Pregnant and Nonpregnant Women with Uncomplicated Plasmodium falciparum Malaria in Tanzania

Mosha

Guidi

Mwingira

et al. 2014

Antimicrob Agents Chemother

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“…Evidence is available from both trials122–127 and observational studies128–131 involving pregnant women (Table 4). Data available indicate that ACTs are relatively safe for the foetus when taken after the first trimester of pregnancy.…”

Section: Prevention and Treatmentmentioning

confidence: 99%

Malaria in Pregnancy

Takem¹,

D’Alessandro

2013

Mediterr J Hematol Infect Dis

123

102

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Pregnant women have a higher risk of malaria compared to non-pregnant women. This review provides an update on knowledge acquired since 2000 on P. falciparum and P.vivax infections in pregnancy. Maternal risk factors for malaria in pregnancy (MiP) include low maternal age, low parity, and low gestational age. The main effects of MIP include maternal anaemia, low birth weight (LBW), preterm delivery and increased infant and maternal mortality.P. falciparum infected erythrocytes sequester in the placenta by expressing surface antigens, mainly variant surface antigen (VAR2CSA), that bind to specific receptors, mainly chondroitin sulphate A. In stable transmission settings, the higher malaria risk in primigravidae can be explained by the non-recognition of these surface antigens by the immune system. Recently, placental sequestration has been described also for P.vivax infections. The mechanism of preterm delivery and intrauterine growth retardation is not completely understood, but fever (preterm delivery), anaemia, and high cytokines levels have been implicated.Clinical suspicion of MiP should be confirmed by parasitological diagnosis. The sensitivity of microscopy, with placenta histology as the gold standard, is 60% and 45% for peripheral and placental falciparum infections in African women, respectively. Compared to microscopy, RDTs have a lower sensitivity though when the quality of microscopy is low RDTs may be more reliable. Insecticide treated nets (ITN) and intermittent preventive treatment in pregnancy (IPTp) are recommended for the prevention of MiP in stable transmission settings. ITNs have been shown to reduce malaria infection and adverse pregnancy outcomes by 28–47%. Although resistance is a concern, SP has been shown to be equivalent to MQ and AQ for IPTp. For the treatment of uncomplicated malaria during the first trimester, quinine plus clindamycin for 7 days is the first line treatment and artesunate plus clindamycin for 7 days is indicated if this treatment fails; in the 2nd and 3rd trimester first line treatment is an artemisinin-based combination therapy (ACT) known to be effective in the region or artesunate and clindamycin for 7 days or quinine and clindamycin. For severe malaria, in the second and third trimester parenteral artesunate is preferred over quinine. In the first trimester, both artesunate and quinine (parenteral) may be considered as options. Nevertheless, treatment should not be delayed and should be started immediately with the most readily available drug.

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“…This could result in lower drug plasma concentrations [24]. Previously published studies have reported a decrease in drug exposure during the later stages of pregnancy for artesunate, artemether, dihydroartemisinin, lumefantrine, sulphadoxine, atovaquone, proguanil and cycloguanil [19,25-31]. Other anti-malarial drugs (e.g.…”

Section: Introductionmentioning

confidence: 99%

A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan

Hoglund

Adam

Hanpithakpong

et al. 2012

Malar J

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BackgroundPregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.MethodSymptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power (MCMP) analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study.ResultsA three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters (80% power and p=0.05). Pregnancy was, therefore, evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen.ConclusionsThe population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.

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Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

Cited by 38 publications

References 51 publications

Population Pharmacokinetics and Clinical Response for Artemether-Lumefantrine in Pregnant and Nonpregnant Women with Uncomplicated Plasmodium falciparum Malaria in Tanzania

Population Pharmacokinetics and Clinical Response for Artemether-Lumefantrine in Pregnant and Nonpregnant Women with Uncomplicated Plasmodium falciparum Malaria in Tanzania

Malaria in Pregnancy

A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan

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