The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria
Rose McGreadyKasia StepniewskaNiklas LindegårdhElizabeth A. AshleyYar LaPratap SinghasivanonNicholas J. WhiteFrançois Nosten
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Keywords:
Artemether/lumefantrine
Lumefantrine
Artemether
Regimen
Dihydroartemisinin
CYP2B6 *6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers
Abstract Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6 *6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers—15 noncarriers ( CYP2B6*1/*1 ) and 15 homozygote carriers ( CYP2B6*6/*6 )—selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3‐day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography–mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52‐1.05]), and total exposure (the area under the plasma concentration‐time curve from time 0 to infinity [AUC 0‐∞ ]) was greater by 35% (1.35 [0.95‐1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC 0‐∞ was 22% lower. On the contrary, artemether‐to‐dihydroartemisinin AUC 0‐∞ ratio was 73% significantly higher (1.73 [1.27‐2.37]). Comparison of lumefantrine exposure and lumefantrine‐to‐desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether‐to‐dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether‐lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition.
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The original title of our article was “Lack of Plasmodium falciparum in Vitro and Genomic Resistance to Dihydroartemisinin in Travelers Returning to France from Africa.” EID’s shortening of the title (1) led to the perception that the letter title was misleading, but it was not on purpose. We have recently tested the 50% inhibitory concentration for artemether of the S769N PfATPase6 isolate that we had kept in liquid nitrogen, and it showed susceptibility.
We underline that the previously reported clinical or parasitologic failures to some artemisinin-based combination therapies (2,3) were not synonymous with the emergence of resistance to artemisinin compounds. In the study by Grandesso et al., a combination of artesunate plus amodiaquine was given to children <5 years of age who lived in an area in which amodiaquine alone was ineffective to adequately treat uncomplicated falciparum malaria in 1 of 3 cases at day 28 (2). Such a combination (artesunate plus amodiaquine) was nearly equivalent in 1 of 3 cases to a 3-day artesunate monotherapy, which may fail to completely cure children because of the short half-life of artesunate. In the study by Bukirwa et al., no recrudescence occurred in patients treated with artesunate plus amodiaquine and only 2 of 199 patients treated with artemether plus lumefantrine experienced recrudescence at day 28 (3). As Birkiwa et al. themselves acknowledged, artemether plus lumefantrine was not administered with food, and it is known that lumefantrine is absorbed better when it is taken with a small amount of fat. Thus, the clinical failures observed did not necessarily reflect P. falciparum resistance to artemisinin compounds.
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ABSTRACT Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively ( P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC (0-8 h) ] ( P < 0.0001) and dihydroartemisinin AUC (60-68 h) ( P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration ( T max ). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.
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The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n = 11) or third (n = 11) trimester with uncomplicated Plasmodium falciparum malaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC0-∞) for lumefantrine was 641 h · mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was time dependent, and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.
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Nevirapine
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Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.
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ABSTRACT The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.
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There are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)s) for artemether and dihydroartemisinin (3,063 and 2,839 μg · h/liter, respectively) were similar to those reported previously in adults with malaria. For lumefantrine, the median AUC(0-∞) (459,980 μg · h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyl-lumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC(0-∞) weighted on in vitro antimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.
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Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.Clinicaltrials.gov NCT01619878.
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