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Applying Modeling and Simulations for Rational Dose Selection of Novel Toll‐Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need
Author(s) -
KloppSchulze Lena,
Shaw Jamie V.,
Dong Jennifer Q.,
Khandelwal Akash,
VazquezMateo Cristina,
Goteti Kosalaram
Publication year - 2022
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2606
Subject(s) - pharmacokinetics , pharmacology , pharmacodynamics , dosing , medicine , systemic lupus erythematosus , population , in vivo , nonmem , cytokine , biology , disease , microbiology and biotechnology , environmental health
Dual toll‐like receptor (TLR) 7 and TLR8 inhibitor enpatoran is under investigation as a treatment for lupus and coronavirus disease 2019 (COVID‐19) pneumonia. Population pharmacokinetic/pharmacodynamic (PopPK/PD) model‐based simulations, using PK and PD (inhibition of ex vivo ‐stimulated interleukin‐6 (IL‐6) and interferon‐α (IFN‐α) secretion) data from a phase I study of enpatoran in healthy participants, were leveraged to inform dose selection for lupus and repurposed for accelerated development in COVID‐19. A two‐compartment PK model was linked to sigmoidal maximum effect (E max ) models with proportional decrease from baseline characterizing the PD responses across the investigated single and multiple doses, up to 200 mg daily for 14 days ( n = 72). Concentrations that maintain 50/60/90% inhibition (IC 50/60/90 ) of cytokine secretion (IL‐6/IFN‐α) over 24 hours were estimated and stochastic simulations performed to assess target coverage under different dosing regimens. Simulations suggested investigating 25, 50, and 100 mg enpatoran twice daily (b.i.d.) to explore the anticipated therapeutic dose range for lupus. With 25 mg b.i.d., > 50% of subjects are expected to achieve 60% inhibition of IL‐6. With 100 mg b.i.d., most subjects are expected to maintain almost complete target coverage for 24 hours (> 80% subjects IC 90,IL‐6 = 15.5 ng/mL; > 60% subjects IC 90,IFN‐α = 22.1 ng/mL). For COVID‐19, 50 and 100 mg enpatoran b.i.d. were recommended; 50 mg b.i.d. provides shorter IFN‐α inhibition (median time above IC 90 = 13 hours/day), which may be beneficial to avoid interference with the antiviral immune response. Utilization of PopPK/PD models initially developed for lupus enabled informed dose selection for the accelerated development of enpatoran in COVID‐19.