Preclinical pharmacokinetic-pharmacodynamic modelling to guide first-time-in-human studies with the anti-miR-103/107, RG-125 (AZD4076)
Monika Sundqvist (1), Madeleine Antonsson (1), Bader Zarrouki (1), Eva-Lotte Lindstedt (1), Andrew Turnbull (1), Tate Owen (2), Kai Liu (2), John Grundy (2) and Brandee Wagner (2)
(1) Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca, Mölndal, Sweden, (2) Regulus Therapeutics, San Diego, California, USA
Objectives: To develop a pharmacokinetic-pharmacodynamic model to describe preclinical data with AZD4076, a novel anti-miR-103/107 GalNAc-conjugated oligonucleotide and predict human dose and time-course of response.
Methods: AZD4076 was administered s.c. once weekly at multiple dose levels to mice (50–450 mg/kg) and non-human primates (NHP; 5–150 mg/kg) in combined pharmacokinetic and toxicology studies. A non-linear pharmacokinetic model was developed describing both plasma and liver exposure for parent drug and its metabolites in mice and NHPs. In a separate series of studies, AZD4076 was dosed once weekly s.c. in DIO mice (1.7–45 mg/kg) and plasma glucose and insulin were measured over time to assess potency and efficacy. The homeostatic model assessment of insulin resistance (HOMA-IR) response in DIO mice was calculated from glucose and insulin, and fit to a turnover model, taking the animal disease progression into account. All data were modelled using non-linear mixed effects modelling with extended least squares estimation (FOCE-ELS) method as implemented in Phoenix 6.4 NMLE 1.3.
Results: A pharmacokinetic model including saturated uptake into liver, predicted observed plasma and liver concentrations of the combined AZD4076 active metabolites in the evaluated animal species well, justifying an allometric approach to predict human pharmacokinetic parameters. The pharmacodynamic model liver IC80 parameter estimate was 10 µM (95% confidence interval: 8-14 µM) in DIO mice and assumed applicable to humans. Allometric scaling was further implemented on the pharmacodynamic model to predict human response over time. The observed time to achieve 50% maximal inhibitory response in AZD4076 treated DIO mice (~5 days) was extrapolated to humans (~30 days), based on reported glucose turnover half-life values in mouse (~3 days) and human (~19 days) studies with thiazolidinediones.
Conclusions: The robust insulin sensitization in DIO mice makes AZD4076 an attractive candidate for investigation of insulin sensitization effects in man. The human PKPD model, albeit assumption-rich, could be further used to guide the design of safety studies as well as early clinical trials, impacting both duration and dosing regimen.