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

Abstract

Despite repeated malaria infection, individuals living in malaria endemic areas remain vulnerable to re-infection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with anti-malarial therapy. This randomized, single-blind, placebo-controlled, single center phase 1 trial investigated the safety, tolerability, 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 aged 18-55 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 three 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 co-administration. Ruxolitinib co-administration resulted in a 3-fold greater pSTAT3 inhibition compared to placebo (geometric mean ratio: 3.01 [90%CI 2.14, 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).