Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine
Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need co-treatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine or artesunate-amodiaquine given with 50m...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Microbiology
2018
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| _version_ | 1797076224948830208 |
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| author | Walimbwa, S Lamorde, M Waitt, C Kaboggoza, J Else, L Byakika-Kibwika, P Amara, A Gini, J Winterberg, M Chiong, J Tarning, J Khoo, S |
| author_facet | Walimbwa, S Lamorde, M Waitt, C Kaboggoza, J Else, L Byakika-Kibwika, P Amara, A Gini, J Winterberg, M Chiong, J Tarning, J Khoo, S |
| author_sort | Walimbwa, S |
| collection | OXFORD |
| description | Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need co-treatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine or artesunate-amodiaquine given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether, dihydroartemisinin, lumefantrine, desbutyl-lumefantrine over 264 hours. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, desethylamodiaquine over 624 hours. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine nor significantly alter AUC for artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine. Co-administration of dolutegravir with artmether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with artesunate-amodiaquine resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above dolutegravir target concentrations of 300ng/mL. Study drugs were well-tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. |
| first_indexed | 2024-03-07T00:01:04Z |
| format | Journal article |
| id | oxford-uuid:75f8704c-cf38-499b-9b11-ed2a82a25867 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:01:04Z |
| publishDate | 2018 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:75f8704c-cf38-499b-9b11-ed2a82a258672022-03-26T20:12:46ZDrug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquineJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:75f8704c-cf38-499b-9b11-ed2a82a25867EnglishSymplectic Elements at OxfordAmerican Society for Microbiology2018Walimbwa, SLamorde, MWaitt, CKaboggoza, JElse, LByakika-Kibwika, PAmara, AGini, JWinterberg, MChiong, JTarning, JKhoo, SAcross sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need co-treatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine or artesunate-amodiaquine given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether, dihydroartemisinin, lumefantrine, desbutyl-lumefantrine over 264 hours. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, desethylamodiaquine over 624 hours. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine nor significantly alter AUC for artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine. Co-administration of dolutegravir with artmether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with artesunate-amodiaquine resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above dolutegravir target concentrations of 300ng/mL. Study drugs were well-tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. |
| spellingShingle | Walimbwa, S Lamorde, M Waitt, C Kaboggoza, J Else, L Byakika-Kibwika, P Amara, A Gini, J Winterberg, M Chiong, J Tarning, J Khoo, S Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine |
| title | Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine |
| title_full | Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine |
| title_fullStr | Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine |
| title_full_unstemmed | Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine |
| title_short | Drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine |
| title_sort | drug interactions between dolutegravir and artemether lumefantrine or artesunate amodiaquine |
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