Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated <i>Plasmodium falciparum</i> Malaria in Uganda

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

doi:10.1038/psp.2013.59

Cited by 45 publications

(64 citation statements)

References 39 publications

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“…These results are comparable with previous findings in pregnant Congolese women, in the same study area, treated with artesunate (24,25). Lower levels of artemether and DHA were also reported in Karen pregnant women (9,10,22,26) and Tanzanian pregnant women treated with artemether-lumefantrine (27).…”

Section: Discussionsupporting

confidence: 90%

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

Onyamboko

Hoglund

Lee

et al. 2020

Antimicrob Agents Chemother

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Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability, and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 nonpregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth and 1, 3, 6, and 12 months. Nonlinear mixed-effects modeling was used to characterize the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range], 3.30 h [1.39 to 7.83 h]) than in nonpregnant women (2.43 h [1.05 to 6.00 h]) (P=0.005). Pregnant women had lower exposures to artemether and dihydroartemisinin than nonpregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to nonpregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and nonpregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure and so could be a promising treatment option in pregnancy in areas with lower rates of malaria transmission and/or emerging drug resistance. (This study has been registered at ClinicalTrials.gov under identifier NCT01916954.)

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Section: Discussionsupporting

confidence: 90%

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

Onyamboko

Hoglund

Lee

et al. 2020

Antimicrob Agents Chemother

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“…Day 7 LF concentration was lower by 27.1% in pregnant women compared with nonpregnant ones. This is similar to what has been reported previously from Africa (Tanzania, Uganda, and Rwanda) and Thailand (McGready et al, 2006;Tarning et al, 2009Tarning et al, , 2013Kloprogge et al, 2013;Mosha et al, 2014;Lohy Das et al, 2018). Lower drug concentrations in pregnant women contribute to lower cure rates and selection of parasite resistance.…”

Section: Discussionsupporting

confidence: 92%

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

et al. 2019

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Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemetherlumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR)corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio 5 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI 5 89.4-96.6) in pregnant women and 95.7% (95% CI 5 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENTThis study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.

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“…Lumefantrine/desbutyl-lumefantrine In agreement with most previous reports, a two compartment disposition model was selected for lumefantrine, whereas a one compartment model was adequate for desbutyl-lumefantrine [49][50][51]. A recent publication used a three compartment disposition model for lumefantrine and a two compartment disposition model for desbutyl-lumefantrine [18].…”

Section: Pharmacokinetic Modelsmentioning

confidence: 94%

Artemether‐lumefantrine co‐administration with antiretrovirals: population pharmacokinetics and dosing implications

Hoglund

Byakika-Kibwika

Lamorde

et al. 2015

Brit J Clinical Pharma

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AIMDrug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.METHODData from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach.RESULTSEfavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.CONCLUSIONThere are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.

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Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda

Cited by 45 publications

References 39 publications

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

Artemether‐lumefantrine co‐administration with antiretrovirals: population pharmacokinetics and dosing implications

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