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

M Farouk Chughlay, Karen I Barnes, Myriam El Gaaloul, Nada Abla, Jörg J Möhrle, Paul Griffin, Paul van Giersbergen, Stephanie E Reuter, Hayley B Schultz, Anita Kress, Peter Tapley, Rebecca A Webster, Timothy Wells, James S McCarthy, Bridget E Barber, Louise Marquart, Michelle J Boyle, Christian R Engwerda, Stephan Chalon, M Farouk Chughlay, Karen I Barnes, Myriam El Gaaloul, Nada Abla, Jörg J Möhrle, Paul Griffin, Paul van Giersbergen, Stephanie E Reuter, Hayley B Schultz, Anita Kress, Peter Tapley, Rebecca A Webster, Timothy Wells, James S McCarthy, Bridget E Barber, Louise Marquart, Michelle J Boyle, Christian R Engwerda, Stephan Chalon

Abstract

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.).

Keywords: artemether-lumefantrine; clinical trial; healthy volunteers; malaria; pharmacokinetics; phase 1 study; ruxolitinib; signal transducer and activator of transcription 3.

Figures

FIG 1
FIG 1
Study design and randomization. PK, pharmacokinetics; EOS, end of study.
FIG 2
FIG 2
Individual participant plasma concentration-time profiles for artemether, dihydroartemisinin, and lumefantrine after coadministration with ruxolitinib or placebo. Dashed lines indicate times where sampling was sparse and do not reflect the actual drug concentrations. AL, artemether-lumefantrine.
FIG 3
FIG 3
Ruxolitinib pharmacokinetics/pharmacodynamics. AL, artemether-lumefantrine. (A) Individual subject ruxolitinib plasma concentration-time profiles. Dashed lines indicate times where sampling was sparse and do not reflect the actual drug concentrations. (B) Individual %pSTAT3 inhibition. Horizontal bars indicate geometric means ± the geometric standard deviations.
FIG 4
FIG 4
Ruxolitinib pharmacokinetic/pharmacodynamic model. (A) Mean ruxolitinib concentration and %pSTAT3 inhibition versus time. (B) Predicted and observed pharmacokinetic/pharmacodynamic relationship between ruxolitinib concentration and %pSTAT3 inhibition. Parameter abbreviations: Ka, absorption rate constant; V/F, apparent volume of distribution of the central compartment; CL/F, apparent clearance; Prop RUV, proportional residual unexplained variability Imax; IC50, ruxolitinib concentration at which there is 50% maximal inhibition; γ Hill coefficient; Add RUV, additive residual unexplained variability.

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