A translational strategy employing physiologically based modelling to predict the pharmacological active dose of RO7119929, an oral prodrug of a targeted cancer immunotherapy TLR7 agonist
Creators: name: Rynn, Caroline
name: Umehara, Kenichi
name: Jiang, Tianyi
name: Ait-Goughoulte, Malika
name: Parrott, Neil
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Science Policy
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences
subject: Hematology
subject: 110309 Infectious Diseases
subject: 60506 Virology
subject: Computational Biology

description: RO7119929 is being developed as an orally administered prodrug of the TLR7-specific agonist and active drug, RO7117418, for the treatment of patients with solid tumours.In this publication, we present a case study wherein the human pharmacokinetics and pharmacological active dose were prospectively predicted following oral administration of the prodrug.A simple translational pharmacokinetic-pharmacodynamic strategy was applied to predict the pharmacological active dose of the prodrug in human. In vivo studies in monkey showed that an unbound plasma exposure of active drug of 1.5 ng/mL elicited secretion of key serum pharmacodynamic cytokine and chemokine biomarkers in monkey. This threshold of 1.5 ng/mL was close to the minimum effective concentration of active drug required to induce cytokine secretion in human peripheral blood mononuclear cells (3 ng/mL).Measured in vitro physicochemical and biochemical properties of the prodrug and active drug were applied as input parameters in physiologically based pharmacokinetic models to predict the pharmacokinetics of active drug after oral dosing of the prodrug in humans. Then, using the PBPK model, a dose which delivered an unbound plasma Cmax in line with the target pharmacodynamic threshold of 1.5 ng/mL was found. This defined the lowest pharmacologically active dose as 3 mg.The prodrug entered the clinic in 2020 in patients with primary or secondary liver cancers. Clear pharmacodynamic, transient, and dose-dependent cytokine induction was observed at prodrug doses &gt; 1 mg. RO7119929 is being developed as an orally administered prodrug of the TLR7-specific agonist and active drug, RO7117418, for the treatment of patients with solid tumours. In this publication, we present a case study wherein the human pharmacokinetics and pharmacological active dose were prospectively predicted following oral administration of the prodrug. A simple translational pharmacokinetic-pharmacodynamic strategy was applied to predict the pharmacological active dose of the prodrug in human. In vivo studies in monkey showed that an unbound plasma exposure of active drug of 1.5 ng/mL elicited secretion of key serum pharmacodynamic cytokine and chemokine biomarkers in monkey. This threshold of 1.5 ng/mL was close to the minimum effective concentration of active drug required to induce cytokine secretion in human peripheral blood mononuclear cells (3 ng/mL). Measured in vitro physicochemical and biochemical properties of the prodrug and active drug were applied as input parameters in physiologically based pharmacokinetic models to predict the pharmacokinetics of active drug after oral dosing of the prodrug in humans. Then, using the PBPK model, a dose which delivered an unbound plasma Cmax in line with the target pharmacodynamic threshold of 1.5 ng/mL was found. This defined the lowest pharmacologically active dose as 3 mg. The prodrug entered the clinic in 2020 in patients with primary or secondary liver cancers. Clear pharmacodynamic, transient, and dose-dependent cytokine induction was observed at prodrug doses &gt; 1 mg.