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A Target-Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults.

ABSTRACT: SPI-62 is a selective and potent small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). SPI-62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose-dependent volume of distribution, nonlinear PK following the first dose, and dose-proportional PK at steady state, as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI-62 is the saturable binding of SPI-62 to its pharmacological target HSD-1, a phenomenon known as target-mediated drug disposition (TMDD). Because of the nonlinear and complex PK of SPI-62, the relationship among SPI-62 dose, exposure, and response is no longer intuitive and consequently dose selection can be challenging. To facilitate dose selection and clinical trial design, in the current study population PK analysis was performed to characterize SPI-62 dose-exposure relationship in humans quantitatively. SPI-62 PK was best characterized by a 2-compartment TMDD model with 3 transit absorption compartments. The model was successfully established to explain the substantial and unusual nonlinear PK of SPI-62 in humans, and it provided adequate fitting for both single- and multiple-dose data. Our modeling work has provided a strong foundation for dose selection in future SPI-62 clinical trials.

SUBMITTER: Wu N

PROVIDER: S-EPMC8596879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

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A Target-Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults.

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