Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC

Onyamboko, Marie; Meshnick, Steven R.; Fleckenstein, Lawrence; Koch, Matthew; Atibu, Joseph; Lokomba, Victor; Douoguih, Macaya; Hemingway-Foday, Jennifer; Wesche, David; Ryder, Robert W.; Bose, Carl; Wright, Linda L.; Tshefu, Antoinette; Capparelli, Edmund V.

doi:10.1186/1475-2875-10-49

Cited by 36 publications

(47 citation statements)

References 30 publications

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“…Three of these drugs are part of the antimalarial drug group (pyrimethamine [199,200], sulfadoxine [199,200], and DHA [192–194,197,198]), two are antithrombotic drugs (unfractionated heparin [113,114] and low-molecular-weight heparin [46,114–117]), one is an antibiotic (ampicillin [67,68]), and the last is an anticancer chemotherapeutic drug (doxorubicin [205,216]). The average quality score of the consistent antibiotic and antithrombotic studies tended to be higher than the quality score of the inconsistent studies from the same group (14.4 versus 11.5, p < 0.05, and 16.4 versus 15.5, p = 0.119, for the antibiotic and antithrombotic drugs, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Inconsistencies in PK parameter changes exist in the AUC and clearance of DHA; a statistically significant reduction in AUC (decreased exposure) and an increase in oral clearance in pregnancy were observed in one study [197], while the change directions were opposite in the other [198]. However, this can be explained by increased disease severity at PK sampling in the latter [198], as systemic exposure of DHA is higher in infected patients with a severe course of malaria than in those with a mild course [198,247].…”

Section: Discussionmentioning

confidence: 99%

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Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

et al. 2016

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BackgroundWomen are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy.Methods and FindingsSystematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown.ConclusionThis systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

et al. 2016

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“…Pharmacokinetic studies, including population pharmacokinetics of PPQ, have been reported in adults and children (10,20,21,25,29,32,33) but not in pregnant women. Plasma concentrations of the artemisinin derivatives artesunate or artemether and their common active metabolite DHA are reported to be low in pregnancy (14,15,17,23), but this has not been studied for DHA-PPQ. In this study, we compared the pharmacokinetic parameters of DHA and PPQ in the treatment of uncomplicated P. falciparum malaria in pregnant and matched nonpregnant women living on the western border of Thailand.…”

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confidence: 99%

Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria

Rijken

McGready

Phyo

et al. 2011

Antimicrob Agents Chemother

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Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P ‫؍‬ 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P ‫؍‬ 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P ‫؍‬ 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P ‫؍‬ 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h ؋ ng/ml versus 1,220 h ؋ ng/ml, P ‫؍‬ 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.In the eastern and western border areas of Thailand, Plasmodium falciparum has developed resistance to almost every antimalarial drug (5). This poses particular problems for the treatment of pregnant women, a group especially vulnerable to P. falciparum infections. The World Health Organization (WHO) recommends the use of artemisinin combination therapy (ACT) (short-course, 3-day treatments) in the second and third trimester of pregnancy (37). However, pregnant women often have lower antimalarial blood concentrations than nonpregnant women and are therefore at risk of undertreatment (13-16, 34, 36). Dihydroartemisinin-piperaquine (DHA-PPQ) is one of the most promising ACTs. It is a coformulation of dihydroartemisinin and piperaquine. Randomized clinical trials in Asia, Africa, and South America indicate excellent tolerability and high cure rates in nonpregnant populations (2-4, 8, 25, 31, 35, 38). Recently, DHA-PPQ was found to be well tolerated and effective in the treatment of multiple recrudescent P. falciparum infections in 50 pregnant women in Thailand (27) and in 104 pregnan...

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“…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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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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Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC

Cited by 36 publications

References 30 publications

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria

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

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