Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria
Abstract Background The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (V...
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2024-11-01
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| Online Access: | https://doi.org/10.1186/s12916-024-03787-0 |
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| author | Azrin N. Abd-Rahman Daniel Kaschek Anne Kümmel Rebecca Webster Adam J. Potter Anand Odedra Stephen D. Woolley Stacey Llewellyn Lachlan Webb Louise Marquart Stephan Chalon Myriam El Gaaloul James S. McCarthy Jörg J. Möhrle Bridget E. Barber |
| author_facet | Azrin N. Abd-Rahman Daniel Kaschek Anne Kümmel Rebecca Webster Adam J. Potter Anand Odedra Stephen D. Woolley Stacey Llewellyn Lachlan Webb Louise Marquart Stephan Chalon Myriam El Gaaloul James S. McCarthy Jörg J. Möhrle Bridget E. Barber |
| author_sort | Azrin N. Abd-Rahman |
| collection | DOAJ |
| description | Abstract Background The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results. Methods Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study. Results For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively. Conclusions These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development. Trial registration This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149. |
| format | Article |
| id | doaj-art-1ad787d5bda644748f24b01ed0c73bbd |
| institution | DOAJ |
| issn | 1741-7015 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | BMC Medicine |
| spelling | doaj-art-1ad787d5bda644748f24b01ed0c73bbd2025-08-20T02:49:17ZengBMCBMC Medicine1741-70152024-11-0122111410.1186/s12916-024-03787-0Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malariaAzrin N. Abd-Rahman0Daniel Kaschek1Anne Kümmel2Rebecca Webster3Adam J. Potter4Anand Odedra5Stephen D. Woolley6Stacey Llewellyn7Lachlan Webb8Louise Marquart9Stephan Chalon10Myriam El Gaaloul11James S. McCarthy12Jörg J. Möhrle13Bridget E. Barber14QIMR Berghofer Medical Research InstituteIntiQuan GmbHIntiQuan GmbHQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteMedicines for Malaria VentureMedicines for Malaria VentureQIMR Berghofer Medical Research InstituteMedicines for Malaria VentureQIMR Berghofer Medical Research InstituteAbstract Background The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results. Methods Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study. Results For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively. Conclusions These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development. Trial registration This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.https://doi.org/10.1186/s12916-024-03787-0ArtefenomelPiperaquineAntimalarialCombinationVolunteer infection studyPharmacokinetics |
| spellingShingle | Azrin N. Abd-Rahman Daniel Kaschek Anne Kümmel Rebecca Webster Adam J. Potter Anand Odedra Stephen D. Woolley Stacey Llewellyn Lachlan Webb Louise Marquart Stephan Chalon Myriam El Gaaloul James S. McCarthy Jörg J. Möhrle Bridget E. Barber Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria BMC Medicine Artefenomel Piperaquine Antimalarial Combination Volunteer infection study Pharmacokinetics |
| title | Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria |
| title_full | Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria |
| title_fullStr | Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria |
| title_full_unstemmed | Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria |
| title_short | Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria |
| title_sort | characterizing the pharmacological interaction of the antimalarial combination artefenomel piperaquine in healthy volunteers with induced blood stage plasmodium falciparum to predict efficacy in patients with malaria |
| topic | Artefenomel Piperaquine Antimalarial Combination Volunteer infection study Pharmacokinetics |
| url | https://doi.org/10.1186/s12916-024-03787-0 |
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