Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults.

Autor: Chughlay MF; Medicines for Malaria Venturegrid.452605.0, Geneva, Switzerland., Barnes KI; Division of Clinical Pharmacology, Department of Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa., El Gaaloul M; Medicines for Malaria Venturegrid.452605.0, Geneva, Switzerland., Abla N; Medicines for Malaria Venturegrid.452605.0, Geneva, Switzerland., Möhrle JJ; Medicines for Malaria Venturegrid.452605.0, Geneva, Switzerland., Griffin P; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia.; Q-Pharm Pty, Ltd., Herston, Queensland, Australia.; University of Queensland, Brisbane, Queensland, Australia.; Mater Health Services, South Brisbane, Queensland, Australia., van Giersbergen P; Van Giersbergen Consulting, Wuenheim, France., Reuter SE; UniSA Clinical and Health Sciences, University of South Australiagrid.1026.5, Adelaide, South Australia, Australia., Schultz HB; UniSA Clinical and Health Sciences, University of South Australiagrid.1026.5, Adelaide, South Australia, Australia., Kress A; Swiss BioQuant, Reinach, Switzerland., Tapley P; TetraQ, Brisbane, Queensland, Australia., Webster RA; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia., Wells T; Medicines for Malaria Venturegrid.452605.0, Geneva, Switzerland., McCarthy JS; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia.; University of Queensland, Brisbane, Queensland, Australia., Barber BE; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia., Marquart L; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia., Boyle MJ; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia., Engwerda CR; QIMR Berghofer Medical Research Institutegrid.1049.c, Brisbane, Queensland, Australia., Chalon S; Medicines for Malaria Venturegrid.452605.0, Geneva, Switzerland.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 Jan 18; Vol. 66 (1), pp. e0158421. Date of Electronic Publication: 2021 Oct 25.
DOI: 10.1128/AAC.01584-21
Abstrakt: 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.).
Databáze: MEDLINE
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