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

Elias C Padilha; Mengbi Yang; Pranav Shah; Amy Q Wang; Jianmin Duan; Joshua K Park; Charles N Zawatsky; May Christine V Malicdan; George Kunos; Malliga R Iyer; Geneviève Gaucher; François Ravenelle; Resat Cinar; Xin Xu

doi:10.1016/j.biopha.2023.115178

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

Biomed Pharmacother. 2023 Dec:168:115178. doi: 10.1016/j.biopha.2023.115178. Epub 2023 Oct 25.

Authors

Affiliations

¹ Drug Metabolism and Pharmacokinetics Core, National Center for Advancing Translational Sciences, Rockville, MD, USA. Electronic address: elias.padilha@nih.gov.
² Drug Metabolism and Pharmacokinetics Core, National Center for Advancing Translational Sciences, Rockville, MD, USA.
³ Inversago Pharma, Montreal, Quebec, Canada.
⁴ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Rockville, MD, USA.
⁵ NIH Undiagnosed Diseases Program, UDP Translational Laboratory, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, MD 20852, USA.
⁷ Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Rockville, MD, USA.
⁸ Drug Metabolism and Pharmacokinetics Core, National Center for Advancing Translational Sciences, Rockville, MD, USA. Electronic address: xin.xu3@nih.gov.

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 (CL_p) and high steady-state volume of distribution (Vd_ss) 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.

Keywords: ADME; Hermansky-Pudlak syndrome; In vivo chiral conversion; PBPK modeling; PK scaling; Pulmonary Fibrosis.

MeSH terms

Animals
Dogs
Hermanski-Pudlak Syndrome* / drug therapy
Humans
Mice
Pulmonary Fibrosis* / diagnostic imaging
Pulmonary Fibrosis* / drug therapy
Rats
Research Design

Substances

MRI-1867

Grants and funding

Z99 TR999999/ImNIH/Intramural NIH HHS/United States