A Randomized Comparison of Artesunate‐Atovaquone‐Proguanil versus Quinine in Treatment for Uncomplicated Falciparum Malaria during Pregnancy

McGready, Rose; Ashley, Elizabeth A.; Moo, Eh; Cho, Thein; Barends, Marion; Hutagalung, Robert; White, Nicholas J.; Nosten, François

doi:10.1086/432551

Cited by 100 publications

(107 citation statements)

References 15 publications

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“…We have reason to believe that AL is more efficacious in Africa than in Southeast Asia where resistance to other antimalarial drugs, such as quinine, mefloquine, and artesunate, has increased (14,49).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, catalytic activity of CYP3A4, CYP2C9, and CYP2A6 enzymes increases during pregnancy (10,11), and these enzymes are responsible for lumefantrine and artemether metabolism (12,13). Hence, it is expected that significant alteration of the pharmacokinetics (PK) of most antimalarial drugs during pregnancy occurs, which may be associated with lower drug concentrations and lower antimalarial cure rate, especially in advanced pregnancy (14)(15)(16). A higher treatment failure rate has indeed been observed for pregnant women compared to nonpregnant ones living in the same area (16).…”

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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: 99%

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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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“…1 To date, resistance to QN remains particularly patchy and rare, [2][3][4][5][6][7][8][9][10][11][12] and only few cases of clinical failure have been reported in Asia and South America. The mechanism underlying QN resistance is not well-understood, and it is probably complex and multigenic.…”

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confidence: 99%

Plasmodium falciparum Na+/H+ Exchanger (pfnhe-1) Genetic Polymorphism in Indian Ocean Malaria-Endemic Areas

Andriantsoanirina

Khim²,

Ratsimbasoa³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. To date, 11 studies conducted in different countries to test the association between Plasmodium falciparum Na + /H + exchanger gene ( pfnhe-1; PF13_0019) polymorphisms and in vitro susceptibility to quinine have generated conflicting data. In this context and to extend our knowledge of the genetic polymorphism of Pfnhe gene, we have sequenced the ms4760 locus from 595 isolates collected in the Comoros (N = 250; an area with a high prevalence of chloroquine and sulfadoxine-pyrimethamine resistance) and Madagascar (N = 345; a low drug-resistance area). Among them, 29 different alleles were observed, including 8 (27%) alleles not previously described. Isolates from the Comoros showed more repeats in block II (DNNND), which some studies have found to be positively associated with in vitro resistance to quinine, compared with isolates from Madagascar. Additional studies are required to better define the mechanisms underlying quinine resistance, which involve multiple gene interactions.Quinine (QN), a natural quinoline derivative compound found in Cinchona bark, has been used for centuries in malaria-endemic regions.1 To date, resistance to QN remains particularly patchy and rare, 2-12 and only few cases of clinical failure have been reported in Asia and South America. The mechanism underlying QN resistance is not well-understood, and it is probably complex and multigenic. Since the seminal work by Ferdig and others 13 in 2004, 11 studies have been conducted in different countries to evaluate implication of ms4760 polymorphisms in QN resistance, [14][15][16][17][18][19][20][21][22][23][24] and conflicting data have been reported, likely because of the different geographical origin of parasites (implying different genetic backgrounds), the type of parasites used (fresh isolates, culture-adapted strains, and reference lines), and the method used to assess in vitro QN susceptibility. 21,25 In this context and to extend our previous work regarding ms4760 polymorphisms in Plasmodium falciparum parasites circulating in malaria-endemic areas in the Indian Ocean, Parasite DNA was extracted from blood spots with Instagene matrix (Bio-Rad, Marnes la Coquette, France) according to the manufacturer's instructions or directly from 100 μL infected blood by the phenol-chloroform method. 26The parasite species was confirmed by real-time polymerase chain reaction (PCR) as described in the work by Mangold and others.27 Amplification and sequencing of the ms4760 locus in the P. falciparum Na + /H + exchanger gene (pfnhe-1) was performed in accordance with the protocol described earlier.14 pfnhe-1 ms4760 alleles were constructed from a full sequence presenting an unambiguous single-allele signal at all positions and used P. falciparum 3D7 (sodium/hydrogen exchanger, Na + , H + antiporter, PF13_0019, XM_001349726) as the reference.Genetic diversity was assessed by Nei's unbiased expected heterozygosity (H e ) from haploid data and calculated as H e = [n/(n -1)][1 − p i ] (n = the number of isolates sampled; p i = the frequency o...

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“…Whereas blood chloroquine and quinine concentrations are relatively unaffected (1, 25), artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, and cycloguanil concentrations are all reduced in later pregnancy (14,(30)(31)(32)(33). The reductions are often substantial, and as a result, antimalarial cure rates in pregnancy for any given antimalarial drug tend to be lower (24, 34).…”

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confidence: 99%

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

Tärning

McGready

Lindegårdh

et al. 2009

Antimicrob Agents Chemother

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114

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Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n ‫؍‬ 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.Pregnancy has considerable effects on the pharmacokinetic properties of many of the drugs used to treat uncomplicated Plasmodium falciparum malaria. Whereas blood chloroquine and quinine concentrations are relatively unaffected (1, 25), artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, and cycloguanil concentrations are all reduced in later pregnancy (14,(30)(31)(32)(33). The reductions are often substantial, and as a result, antimalarial cure rates in pregnancy for any given antimalarial drug tend to be lower (24, 34). Unfortunately, pregnant women are especially vulnerable to malaria and the fetus is adversely affected.The fixed combination of artemether and lumefantrine is the result of research undertaken by Chinese scientists and has become the most widely used coformulated artemisinin-based combination therapy (ACT). Artemether-lumefantrine has proved effective (cure rates, Ͼ97%) and safe in adults and children in trials conducted throughout the areas of the world affected by malaria (2,13,15,20,23,35,43,44,59). There is a reluctance to prescribe new drugs to pregnant women, and there have been concerns over the safety of artemisinin derivatives in early pregnancy. The curr...

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A Randomized Comparison of Artesunate‐Atovaquone‐Proguanil versus Quinine in Treatment for Uncomplicated Falciparum Malaria during Pregnancy

Cited by 100 publications

References 15 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

Plasmodium falciparum Na+/H+ Exchanger (pfnhe-1) Genetic Polymorphism in Indian Ocean Malaria-Endemic Areas

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

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