Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.
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 enroll...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2006
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| _version_ | 1797073742049837056 |
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| author | Price, R Uhlemann, A van Vugt, M Brockman, A Hutagalung, R Nair, S Nash, D Singhasivanon, P Anderson, T Krishna, S White, N Nosten, F |
| author_facet | Price, R Uhlemann, A van Vugt, M Brockman, A Hutagalung, R Nair, S Nash, D Singhasivanon, P Anderson, T Krishna, S White, N Nosten, F |
| author_sort | Price, R |
| collection | OXFORD |
| description | 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 concentration(50) (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. |
| first_indexed | 2024-03-06T23:26:23Z |
| format | Journal article |
| id | oxford-uuid:6a819529-2a7c-48e7-9294-9e6b81d51920 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:26:23Z |
| publishDate | 2006 |
| record_format | dspace |
| spelling | oxford-uuid:6a819529-2a7c-48e7-9294-9e6b81d519202022-03-26T18:57:58ZMolecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6a819529-2a7c-48e7-9294-9e6b81d51920EnglishSymplectic Elements at Oxford2006Price, RUhlemann, Avan Vugt, MBrockman, AHutagalung, RNair, SNash, DSinghasivanon, PAnderson, TKrishna, SWhite, NNosten, FBACKGROUND: 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 concentration(50) (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. |
| spellingShingle | Price, R Uhlemann, A van Vugt, M Brockman, A Hutagalung, R Nair, S Nash, D Singhasivanon, P Anderson, T Krishna, S White, N Nosten, F Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. |
| title | Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. |
| title_full | Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. |
| title_fullStr | Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. |
| title_full_unstemmed | Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. |
| title_short | Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. |
| title_sort | molecular and pharmacological determinants of the therapeutic response to artemether lumefantrine in multidrug resistant plasmodium falciparum malaria |
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