Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria

Ric Price, A Uhlemann, M Vanvugt, A Brockman, R Hutagalung, Shalini Nair, D Nash, Pratap Singhasivanon, Tim Anderson, Sanjeev Krishna, N WHITE, F NOSTEN

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background. Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). Methods. On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. Results. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration50 (P = .001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P = .008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. Conclusions. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic. � 2006 by the Infectious Diseases Society of America. All rights reserved.
    Original languageEnglish
    Pages (from-to)1570-1577
    Number of pages8
    JournalClinical Infectious Diseases
    Volume42
    Issue number11
    Publication statusPublished - 2006

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    Falciparum Malaria
    Pharmacology
    Confidence Intervals
    Therapeutics
    Treatment Failure
    artemether
    lumefantrine
    Thailand
    Malaria
    Real-Time Polymerase Chain Reaction
    Parasites
    Pharmacokinetics
    Odds Ratio
    High Pressure Liquid Chromatography
    Prospective Studies
    Recurrence
    Sensitivity and Specificity
    Polymerase Chain Reaction

    Cite this

    Price, Ric ; Uhlemann, A ; Vanvugt, M ; Brockman, A ; Hutagalung, R ; Nair, Shalini ; Nash, D ; Singhasivanon, Pratap ; Anderson, Tim ; Krishna, Sanjeev ; WHITE, N ; NOSTEN, F. / Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria. In: Clinical Infectious Diseases. 2006 ; Vol. 42, No. 11. pp. 1570-1577.
    @article{62227e4154704d1bb2d2688635fd10f7,
    title = "Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria",
    abstract = "Background. Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). Methods. On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. Results. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13{\%} (95{\%} confidence interval [CI], 9.6{\%}-17{\%}) for the 4-dose regimen and 3.2{\%} (95{\%} CI, 1.8{\%}-4.6{\%}) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95{\%} CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration50 (P = .001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95{\%} CI, 1.4-11; P = .008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95{\%} CI, 5.5-53), allowing prediction of treatment failure with 75{\%} sensitivity and 84{\%} specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91{\%} of treated patients. Conclusions. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic. � 2006 by the Infectious Diseases Society of America. All rights reserved.",
    keywords = "artemether plus benflumetol, artesunate, halofantrine, mefloquine, quinine, adolescent, article, child, concentration response, disease association, drug blood level, drug dose regimen, drug efficacy, drug safety, drug sensitivity, drug tolerability, female, gene, high performance liquid chromatography, human, in vitro study, major clinical study, malaria, male, molecular biology, multidrug resistance, pfmdr1 gene, Plasmodium falciparum, priority journal, prospective study, quantitative analysis, reverse transcription polymerase chain reaction, risk factor, sensitivity and specificity, Thailand, treatment failure, Adolescent, Adult, Animals, Antimalarials, Artemisinins, ATP-Binding Cassette Transporters, Child, Child, Preschool, Drug Administration Schedule, Drug Resistance, Drug Therapy, Combination, Ethanolamines, Female, Fluorenes, Humans, Malaria, Falciparum, Male, Polymorphism, Single Nucleotide, Protozoan Proteins",
    author = "Ric Price and A Uhlemann and M Vanvugt and A Brockman and R Hutagalung and Shalini Nair and D Nash and Pratap Singhasivanon and Tim Anderson and Sanjeev Krishna and N WHITE and F NOSTEN",
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    Price, R, Uhlemann, A, Vanvugt, M, Brockman, A, Hutagalung, R, Nair, S, Nash, D, Singhasivanon, P, Anderson, T, Krishna, S, WHITE, N & NOSTEN, F 2006, 'Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria', Clinical Infectious Diseases, vol. 42, no. 11, pp. 1570-1577.

    Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria. / Price, Ric; Uhlemann, A; Vanvugt, M; Brockman, A; Hutagalung, R; Nair, Shalini; Nash, D; Singhasivanon, Pratap; Anderson, Tim; Krishna, Sanjeev; WHITE, N; NOSTEN, F.

    In: Clinical Infectious Diseases, Vol. 42, No. 11, 2006, p. 1570-1577.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Molecular and pharmacological determinants of the therapeutic response to artemether-lumefentrine in multidrug-resistant Plasmodium falciparum malaria

    AU - Price, Ric

    AU - Uhlemann, A

    AU - Vanvugt, M

    AU - Brockman, A

    AU - Hutagalung, R

    AU - Nair, Shalini

    AU - Nash, D

    AU - Singhasivanon, Pratap

    AU - Anderson, Tim

    AU - Krishna, Sanjeev

    AU - WHITE, N

    AU - NOSTEN, F

    PY - 2006

    Y1 - 2006

    N2 - Background. Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). Methods. On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. Results. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration50 (P = .001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P = .008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. Conclusions. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic. � 2006 by the Infectious Diseases Society of America. All rights reserved.

    AB - Background. Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). Methods. On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. Results. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration50 (P = .001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P = .008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. Conclusions. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic. � 2006 by the Infectious Diseases Society of America. All rights reserved.

    KW - artemether plus benflumetol

    KW - artesunate

    KW - halofantrine

    KW - mefloquine

    KW - quinine

    KW - adolescent

    KW - article

    KW - child

    KW - concentration response

    KW - disease association

    KW - drug blood level

    KW - drug dose regimen

    KW - drug efficacy

    KW - drug safety

    KW - drug sensitivity

    KW - drug tolerability

    KW - female

    KW - gene

    KW - high performance liquid chromatography

    KW - human

    KW - in vitro study

    KW - major clinical study

    KW - malaria

    KW - male

    KW - molecular biology

    KW - multidrug resistance

    KW - pfmdr1 gene

    KW - Plasmodium falciparum

    KW - priority journal

    KW - prospective study

    KW - quantitative analysis

    KW - reverse transcription polymerase chain reaction

    KW - risk factor

    KW - sensitivity and specificity

    KW - Thailand

    KW - treatment failure

    KW - Adolescent

    KW - Adult

    KW - Animals

    KW - Antimalarials

    KW - Artemisinins

    KW - ATP-Binding Cassette Transporters

    KW - Child

    KW - Child, Preschool

    KW - Drug Administration Schedule

    KW - Drug Resistance

    KW - Drug Therapy, Combination

    KW - Ethanolamines

    KW - Female

    KW - Fluorenes

    KW - Humans

    KW - Malaria, Falciparum

    KW - Male

    KW - Polymorphism, Single Nucleotide

    KW - Protozoan Proteins

    M3 - Article

    VL - 42

    SP - 1570

    EP - 1577

    JO - Clinical Infectious Diseases

    JF - Clinical Infectious Diseases

    SN - 1058-4838

    IS - 11

    ER -