Cargando…
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults
Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This ra...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765294/ https://www.ncbi.nlm.nih.gov/pubmed/34694880 http://dx.doi.org/10.1128/AAC.01584-21 |
_version_ | 1784634310514442240 |
---|---|
author | Chughlay, M. Farouk Barnes, Karen I. El Gaaloul, Myriam Abla, Nada Möhrle, Jörg J. Griffin, Paul van Giersbergen, Paul Reuter, Stephanie E. Schultz, Hayley B. Kress, Anita Tapley, Peter Webster, Rebecca A. Wells, Timothy McCarthy, James S. Barber, Bridget E. Marquart, Louise Boyle, Michelle J. Engwerda, Christian R. Chalon, Stephan |
author_facet | Chughlay, M. Farouk Barnes, Karen I. El Gaaloul, Myriam Abla, Nada Möhrle, Jörg J. Griffin, Paul van Giersbergen, Paul Reuter, Stephanie E. Schultz, Hayley B. Kress, Anita Tapley, Peter Webster, Rebecca A. Wells, Timothy McCarthy, James S. Barber, Bridget E. Marquart, Louise Boyle, Michelle J. Engwerda, Christian R. Chalon, Stephan |
author_sort | Chughlay, M. Farouk |
collection | PubMed |
description | Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.) |
format | Online Article Text |
id | pubmed-8765294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-87652942022-01-24 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults Chughlay, M. Farouk Barnes, Karen I. El Gaaloul, Myriam Abla, Nada Möhrle, Jörg J. Griffin, Paul van Giersbergen, Paul Reuter, Stephanie E. Schultz, Hayley B. Kress, Anita Tapley, Peter Webster, Rebecca A. Wells, Timothy McCarthy, James S. Barber, Bridget E. Marquart, Louise Boyle, Michelle J. Engwerda, Christian R. Chalon, Stephan Antimicrob Agents Chemother Clinical Therapeutics Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.) American Society for Microbiology 2022-01-18 /pmc/articles/PMC8765294/ /pubmed/34694880 http://dx.doi.org/10.1128/AAC.01584-21 Text en Copyright © 2022 Chughlay et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Clinical Therapeutics Chughlay, M. Farouk Barnes, Karen I. El Gaaloul, Myriam Abla, Nada Möhrle, Jörg J. Griffin, Paul van Giersbergen, Paul Reuter, Stephanie E. Schultz, Hayley B. Kress, Anita Tapley, Peter Webster, Rebecca A. Wells, Timothy McCarthy, James S. Barber, Bridget E. Marquart, Louise Boyle, Michelle J. Engwerda, Christian R. Chalon, Stephan Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults |
title | Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults |
title_full | Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults |
title_fullStr | Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults |
title_full_unstemmed | Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults |
title_short | Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults |
title_sort | safety, tolerability, pharmacokinetics, and pharmacodynamics of coadministered ruxolitinib and artemether-lumefantrine in healthy adults |
topic | Clinical Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765294/ https://www.ncbi.nlm.nih.gov/pubmed/34694880 http://dx.doi.org/10.1128/AAC.01584-21 |
work_keys_str_mv | AT chughlaymfarouk safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT barneskareni safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT elgaaloulmyriam safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT ablanada safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT mohrlejorgj safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT griffinpaul safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT vangiersbergenpaul safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT reuterstephaniee safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT schultzhayleyb safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT kressanita safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT tapleypeter safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT websterrebeccaa safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT wellstimothy safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT mccarthyjamess safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT barberbridgete safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT marquartlouise safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT boylemichellej safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT engwerdachristianr safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults AT chalonstephan safetytolerabilitypharmacokineticsandpharmacodynamicsofcoadministeredruxolitinibandartemetherlumefantrineinhealthyadults |