In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis - 11/11/23
, Mengbi Yang a, 1, Pranav Shah a, Amy Q. Wang a, Jianmin Duan b, Joshua K. Park c, Charles N. Zawatsky c, May Christine V. Malicdan d, George Kunos c, Malliga R. Iyer e, Geneviève Gaucher b, François Ravenelle b, Resat Cinar f, Xin Xu a, ⁎ Abstract |
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that affects lysosome-related organelles, often leading to fatal pulmonary fibrosis (PF). The search for a treatment for HPS pulmonary fibrosis (HPSPF) is ongoing. S-MRI-1867, a dual cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) inhibitor, has shown great promise for the treatment of several fibrotic diseases, including HPSPF. In this study, we investigated the in vitro ADME characteristics of S-MRI-1867, as well as its pharmacokinetic (PK) properties in mice, rats, dogs, and monkeys. S-MRI-1867 showed low aqueous solubility (< 1 µg/mL), high plasma protein binding (>99%), and moderate to high metabolic stability. In its preclinical PK studies, S-MRI-1867 exhibited moderate to low plasma clearance (CLp) and high steady-state volume of distribution (Vdss) across all species. Despite the low solubility and P-gp efflux, S-MRI-1867 showed great permeability and metabolic stability leading to a moderate bioavailability (21-60%) across mouse, rat, dog, and monkey. Since the R form of MRI-1867 is CB1R-inactive, we investigated the potential conversion of S-MRI-1867 to R-MRI-1867 in mice and found that the chiral conversion was negligible. Furthermore, we developed and validated a PBPK model that adequately fits the PK profiles of S-MRI-1867 in mice, rats, dogs, and monkeys using various dosing regimens. We employed this PBPK model to simulate the human PK profiles of S-MRI-1867, enabling us to inform human dose selection and support the advancement of this promising drug candidate in the treatment of HPSPF.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | S-MRI-1867: CB1R/iNOS inhibitor shows low solubility and high protein binding, impacting formulation and bioavailability. |
• | There is minimal chiral conversion of S-MRI-1867 to the R- inactive form, ensuring sustained efficacy of the stereoisomer. |
• | S-MRI-1867 exhibits high permeability, moderate clearance, and large volume of distribution in preclinical studies. |
• | The PBPK model accurately predicts PK profiles across species, supporting interspecies scalability. |
• | The validated PBPK model enables simulation of human PK profiles, achieving effective concentrations at manageable doses. |
Abbreviations : HPS, PF, HPSPF, CB1R, iNOS, IVIVE, SGF, SIF, PAMPA, SC, ESF, PBPK, FE
Keywords : PBPK modeling, PK scaling, In vivo chiral conversion, Hermansky-Pudlak syndrome, Pulmonary Fibrosis, ADME
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Vol 168
Article 115178- décembre 2023 Retour au numéro
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