Importance of Target‐Mediated Drug Disposition (TMDD) of Small‐Molecule Compounds and Its Impact on Drug Development—Example of the Class Effect of HSD‐1 Inhibitors

An, Guohua; Katz, David A.

doi:10.1002/jcph.2185

Cited by 6 publications

(12 citation statements)

References 41 publications

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“…The nonlinear characteristics observed in BI 187004 are consistent with typical PK and PD behaviors of small-molecule compounds undergoing TMDD with targets located in tissues. [20][21][22][23] Furthermore, similar nonlinear PK profiles have been observed in other 11β-HSD1 inhibitors, including ABT-384, 24,25 SPI-62, 26,27 MK-0916, 28 and BMS-823778. 29 Specifically, for ABT-384, SPI-62, and MK-0916, TMDD models have been developed to explain their complex nonlinear PK in both single-and multiple-dose regimens.…”

Section: Introductionsupporting

confidence: 71%

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target‐Mediated Drug Disposition Model

Yuan,

2024

The Journal of Clinical Pharma

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BI 187004, a selective small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β‐HSD1 inhibition (50%) was detected in a very low‐dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose‐dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target‐mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high‐affinity and low‐capacity target 11β‐HSD1. The non‐intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small‐molecule compound. Among the various models explored, the best model was a two‐compartment TMDD model with three transit absorption components. The final model provides insights into 11β‐HSD1 binding‐related parameters for BI 187004, including the total amount of 11β‐HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM−1h−1), and the first‐order dissociation rate constant (estimated to be 0.11 h−1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials.

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Section: Introductionsupporting

confidence: 71%

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target‐Mediated Drug Disposition Model

Yuan,

2024

The Journal of Clinical Pharma

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“…The TMDD-PD modeling and simulation results provide a strong foundation for model-informed development of SPI-62. In addition, since TMDD has been reported to be a class effect of HSD-1 inhibitors [ 24 ], the TMDD-PD model that we developed for SPI-62 has potential to be utilized for other members of the class to facilitate interpretation of their PK and PD data as well as future clinical trial design.…”

Section: Discussionmentioning

confidence: 99%

“…For PK evaluation, serial blood samples were collected at 0.5, 1, 1. 5,2,3,4,6,8,10,12,18,24,36,48, and 72 h after oral dose administration for the 1, 3, and 10 mg cohorts, while two additional blood samples were collected at 96 and 120 h after dose administration for the 6 mg cohort. SPI-62 plasma concentrations were determined by a validated high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.…”

Section: Data Sourcementioning

confidence: 99%

“…The LLOQ was 4 pg/mL [9]. For PD assessment, urine samples from the first-morning void were collected at predose, and on Days 1,2,3,4,5,6,8,10,12,14,16,18,20,22,23,24,25,26, and 27 for subjects administered 0.7 or 2 mg SPI-62. Urine samples from the first morning void were collected at predose, and on Days 1, 8, 10, 12, 14, 16, 18, 20, 21 for subjects administered 0.2 or 0.4 mg SPI-62 [9].…”

Section: Data Sourcementioning

confidence: 99%

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Population Target-Mediated Pharmacokinetic/Pharmacodynamic Modeling to Evaluate SPI-62 Exposure and Hepatic 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Inhibition in Healthy Adults

Katz

2023

Clin Pharmacokinet

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Introduction SPI-62 is a small-molecule 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor exhibiting complicated nonlinear pharmacokinetics (PK) in human. Previously, we developed a target-mediated drug disposition (TMDD) model to characterize the substantial nonlinear PK of SPI-62. Objective The aim of the current analysis was to perform population PK/PD analysis to further link SPI-62 exposure (i.e., PK) with its response (i.e., inhibition of hepatic HSD-1 activity) to gain a quantitative understanding of the SPI-62 dose-exposure-response relationship. Methods PK and PD data from the first-in-human (FIH) clinical trials, including single ascending dose (SAD) and multiple ascending dose (MAD) studies, were used for model development. During the model development process, the final model selection was based on biological and physiological plausibility, goodness-of-fit plots, stability of parameter estimates, and objective function value. The nonlinear-mixed effect modeling (NONMEM) software was used for both the implementation of the PK/PD model and model simulation. SPI-62 plasma levels and hepatic HSD-1 inhibition over time following various dose regimens were simulated. Results The final model was a two-compartment TMDD model component for SPI-62 and an inhibitory I max model component for hepatic HSD-1 activity. The TMDD-hepatic PD model that we established adequately characterized all remarkable PK and PD behaviors of SPI-62, such as extremely low plasma exposures following the first low doses, nonlinear PK turned into linear PK after repeated low doses, and substantial and long-lasting hepatic HSD-1 inhibition following low doses. SPI-62 was estimated to bind to the target with a second-order association rate constant ( K on ) of 8.43 nM −1 h −1 and first-order dissociation rate constant ( K off ) value of 0.229 h −1 , indicating that SPI-62 binds rapidly to, and dissociates slowly from, its pharmacological target. The estimated target capacity ( R tot ) of 5460 nmol corresponds to approximately 2.2 mg of SPI-62, which comports well with the dose range in which PK nonlinearity is prominent. Model simulation results reveal that a 6 mg once-daily regimen can lead to long-lasting and substantial hepatic HSD-1 inhibition. Conclusions A population TMDD-PD model that explains SPI-62 nonlinear PK and hepatic HSD-1 inhibition following different dose regimens in healthy adults was successfully established. Our simulation results provide a solid foundation for model-informed development of SPI-62. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-0...

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“…To be specific, 11β-HSD1 is a predominant reductase, mediating regeneration of MPL from MPN, while 11β-HSD2 is an exclusive dehydrogenase, inactivating MPL to MPN. A recently raised target-mediated drug disposition (TMDD) phenomenon for 11β-HSD1 complicates the reversible metabolism further (An and Katz, 2023). This is evidenced by the high-affinity and low-capacity binding of 11β-HSD1 and its inhibitor and the accordingly concentration-time profiles with typical TMDD features (Wu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling: The Reversible Metabolism and Tissue-Specific Partitioning of Methylprednisolone and Methylprednisone in Rats

Yu,

Jusko

2024

Drug Metab Dispos

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The pharmacokinetics (PK) of methylprednisolone (MPL) exhibited tissue-specific saturable binding and reversible conversion with its metabolite, methylprednisone (MPN). Blood and 11 tissues were collected in male rats after intravenous (IV) bolus doses of 50 mg/kg MPL and 20 mg/kg MPN and upon IV infusion of MPL and MPN at 0.3, 3, and 10 mg/h/kg. The concentrations of MPL and MPN were simultaneously measured. A comprehensive physiologically based pharmacokinetic (PBPK) model was applied to describe the plasma and tissue profiles and estimate PK parameters of the MPL/MPN interconversion system. Both dosed and formed MPL and MPN were in rapid equilibrium or achieved steady-state rapidly in plasma and tissues. MPL tissue partitioning was nonlinear with highest capacity in liver (322.9 ng/mL), followed by kidney, heart, intestine, skin, spleen, bone, brain, muscle, and lowest in adipose (2.74 ng/mL), and displayed high penetration in lung. The tissue partition coefficient of MPN was linear but widely variable (0.15~5.38

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Importance of Target‐Mediated Drug Disposition (TMDD) of Small‐Molecule Compounds and Its Impact on Drug Development—Example of the Class Effect of HSD‐1 Inhibitors

Cited by 6 publications

References 41 publications

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target‐Mediated Drug Disposition Model

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target‐Mediated Drug Disposition Model

Population Target-Mediated Pharmacokinetic/Pharmacodynamic Modeling to Evaluate SPI-62 Exposure and Hepatic 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Inhibition in Healthy Adults

Physiologically Based Pharmacokinetic Modeling: The Reversible Metabolism and Tissue-Specific Partitioning of Methylprednisolone and Methylprednisone in Rats

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