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

Nan Wu; David A Katz; Guohua An

doi:10.1002/jcph.1925

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

Nan Wu, David A Katz and Guohua An

Journal of clinical pharmacology, Vol.61(11), pp.1442-1453

11/2021

DOI: 10.1002/jcph.1925

PMCID: PMC8596879

PMID: 34110620

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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.

11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors

Benzamides - pharmacokinetics

Dose-Response Relationship, Drug

Double-Blind Method

Humans

Models, Biological

Triazoles - pharmacokinetics

Details

Title: Subtitle: A Target-Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults
Creators: Nan Wu - University of Iowa
David A Katz - Sparrow Pharmaceuticals, Inc., Portland, Oregon, USA
Guohua An - University of Iowa
Resource Type: Journal article
Publication Details: Journal of clinical pharmacology, Vol.61(11), pp.1442-1453
DOI: 10.1002/jcph.1925
PMID: 34110620
PMCID: PMC8596879
NLM abbreviation: J Clin Pharmacol
ISSN: 0091-2700
eISSN: 1552-4604
Language: English
Date published: 11/2021
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; General Internal Medicine; Internal Medicine
Record Identifier: 9984365904102771

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