Randomized Comparison of Chloroquine plus Sulfadoxine-Pyrimethamine versus Artesunate plus Mefloquine versus Artemether-Lumefantrine in the Treatment of Uncomplicated Falciparum Malaria in the Lao People's Democratic Republic

Mayxay, Mayfong; Khanthavong, Maniphone; Lindegårdh, Niklas; Keola, Siamphay; Barends, Marion; Pongvongsa, Tiengkham; Yapom, Ratsuda; Annerberg, Anna; Phompida, Samlane; Phetsouvanh, Rattanaxay; White, Nicholas J.; Newton, Paul N.

doi:10.1086/424512

Cited by 67 publications

(79 citation statements)

References 29 publications

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“…These predicted day 7 capillary plasma concentrations were approximately equivalent to the median venous plasma concentrations of 310 ng/ml (range, 94 to 1,364 ng/ml) determined by using the previously characterized relationship between capillary and venous concentrations (49). This is considerably lower than the corresponding values previously reported in nonpregnant adults and pediatric patients with multiresistant malaria in Thailand, Cambodia, and the Lao People's Democratic Republic (10,29,42,47). Price et al (42) reported a median day 7 venous plasma lumefantrine concentration of 528 ng/ml (range, 49 to 5,175 ng/ml) in Karen patients (n ϭ 201) receiving the same standard treatment of artemether-lumefantrine.…”

Section: Discussionsupporting

confidence: 48%

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

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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Section: Discussionsupporting

confidence: 48%

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

114

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“…These results were in accordance with those of previous randomized studies reporting Day-42 cure-rate data with A-L in adolescents and adults from areas of multi-drug resistance, and applying a similarly conservative approach for analysis. 29,30 In conclusion, over a 6-week observation period, A-L administered twice daily for three consecutive days was well tolerated and highly efficacious for the treatment of acute uncomplicated P. falciparum malaria. Neither ABR latencies nor pure-tone thresholds showed clinical or statistical evidence of an effect of A-L on auditory functioning, confirming previous studies.…”

Section: Discussionmentioning

confidence: 87%

Randomized, Prospective, Three-Arm Study to Confirm the Auditory Safety and Efficacy of Artemether-Lumefantrine in Colombian Patients with Uncomplicated Plasmodium falciparum Malaria

Carrasquilla

Barón

Monsell³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine ( N = 159), atovaquone-proguanil ( N = 53), or artesunate-mefloquine ( N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is ≥ 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% ( P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria.

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“…By use of intention-to-treat analysis, the 42-day cure rates, adjusted for re-infections, were 100, 97 and 93% for the groups receiving AS-MQ, AL, and CQ-SP, respectively. This study demonstrates that oral AS-MQ and AL were highly effective for the treatment of uncomplicated falciparum malaria at the time (Mayxay et al, 2004). Monitoring of therapeutic efficacy and tolerability of AL versus AS-MQ in Senegal showed that the cure rate was 98.5% in the AS-MQ group versus 98.2% in the AL group at day 42 (p = 1).…”

Section: -Day In Vivo Protocol To Test Acts Efficacymentioning

confidence: 75%

“…The 28-day follow-up protocol (Chanda et al, 2006;Denis et al, 2002;Marquino et al, 2003) or 42-day follow-up protocol (Leang et al, 2015;Mårtensson et al, 2005;Mayxay et al, 2004;Valecha et al, 2010;Yeka et al, 2008) were usually used. Few studies used 63-day follow-up protocols for efficacy monitoring of ACTs containing a long half-life partner drug (Sodiomon et al, 2016;Valecha et al, 2010).…”

Section: In Vivo Act Efficacy Evaluationmentioning

confidence: 99%

“…versus AQ-MQ versus CQ-SP in Lao People's Democratic Republic showed that the cure rates, excluding patients who were lost to follow-up or experienced reinfections, were 100, 97 and 92% for subjects receiving AS-MQ, AL, and CQ-SP, respectively (Mayxay et al, 2004). By use of intention-to-treat analysis, the 42-day cure rates, adjusted for re-infections, were 100, 97 and 93% for the groups receiving AS-MQ, AL, and CQ-SP, respectively.…”

Section: -Day In Vivo Protocol To Test Acts Efficacymentioning

confidence: 99%

See 1 more Smart Citation

Methods for monitoring artemisinin-based combination therapies efficacy

Dama¹,

Djimdé²,

Doumbo³

2017

Clin. Rev. Opinions

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Plasmodium falciparum resistance to artemisinin and its derivatives is spreading in South-East Asia, and there is growing concern that this may reach other endemic countries. Methods used to assess P. falciparum resistance to artemisinin-based combination therapies (ACTs) are multiple and often divergent. This paper is a review of online accessible research publications from the past 20 years on ACTs, ranging from in vivo, in vitro/ex-vivo, molecular markers and pharmacokinetics studies. We highlight the procedures of the four main methods used for ACTs e f f i c a c y testing and provide a summary of published data. This review indicates that the most used method for ACT efficacy testing is the in vivo 28 days follow-up with molecular correction; the most widely used and reliable in vitro and ex-vivo method for artemisinin phenotyping is the ring stage survival assay from 0 to 3 h ring (RSA 0-3h ), and the main molecular marker of P. falciparum resistance to artemisinins are mutations on P. falciparum Kelch 13 propeller domain. Day 7 pharmacokinetics could help to predict resistance to artemether-lumefantrine and dihydroartemisinin-piperaquine. Findings from this review support that the combination of in vivo, in vitro/ex-vivo, molecular markers of drug resistance and day 7 PK levels of the partner drugs may be required for the optimal surveillance of artemisinin-based combination therapy efficacy in the field.

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Randomized Comparison of Chloroquine plus Sulfadoxine-Pyrimethamine versus Artesunate plus Mefloquine versus Artemether-Lumefantrine in the Treatment of Uncomplicated Falciparum Malaria in the Lao People's Democratic Republic

Abstract: Oral artesunate plus mefloquine and artemether-lumefantrine are highly effective for the treatment of uncomplicated falciparum malaria in Laos.

Cited by 67 publications

References 29 publications

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

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

Randomized, Prospective, Three-Arm Study to Confirm the Auditory Safety and Efficacy of Artemether-Lumefantrine in Colombian Patients with Uncomplicated Plasmodium falciparum Malaria

Methods for monitoring artemisinin-based combination therapies efficacy

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