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 exposures at low doses; dose-dependent This article is protected by copyright. All rights reserved. 2 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). Due to 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 doseexposure relationship in humans quantitatively. SPI-62 PK was best characterized by a twocompartment 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.

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

“…22 However, the observed BMS-823778 C max value was only 19 ng/mL in the 5-mg dose group and was undetectable in the 0.5-mg dose group. 22 Results from the FIH MAD study showed that the nonlinear pharmacokinetics of BMS-823778 at low doses observed on day 1 disappeared after repeated doses, as reflected by the dose-proportional pharmacokinetics across all doses on day 14 22 ; this unusual phenomenon was also observed for ABT-384, 11 SPI-62, 32 and MK-0916. 23 Similarly, BMS-823778 accumulation ratios were also dose dependent, with unusually high values for the low-dose groups.…”

“…Interestingly, the nonlinear pharmacokinetics exhibited after the first dose disappeared after repeated doses, as reflected by the superimposed plots on day 7 across In these 2 dose groups, SPI-62 was given as single dose first (day 1), followed by a 6-day washout (days 1 to 6), and then 14 days QD doses (days 7 to 20). Figure 3a-c was adapted from Wu et al 32 Figure 3d was adapted from Bellaire et al 21 all doses evaluated (Figure 2a). Figure 2b shows that the accumulation ratio, calculated as the C max of ABT-384 on day 7 over the C max of ABT-384 on day 1, was >41 in the 1-mg dose group, 24.2 in the 2-mg dose group, 11.3 in the 4-mg dose group, and dropped to 1 to 2 in the higher dose groups.…”

“…As for ABT-384, substantial nonlinear pharmacokinetics of SPI-62 were also observed in FIH SAD and MAD clinical studies. 21,32 After single oral dose regimens of 1, 3, 6, 10, 30, and 60 mg, the pharmacokinetics of SPI-62 were nonlinear at low doses but switched to linear when SPI-62 was administered at doses ≥10 mg (Figure 3a). 21 The nonlinearity of SPI-62 following single low doses was reflected by the unusually low plasma exposures of SPI-62.…”

“…For example, consistent B max values across multiple compounds might indicate the approximate molar quantity of the target enzyme HSD-1 in the body. 11,23,32 Recognizing TMDD in small-molecule compounds is important as the information can be leveraged to select the appropriate dose regimen, improve clinical trial design, as well as predict pharmacological target occupancy. As compounds exhibiting TMDD may have order/sequence effects, extra caution is needed when carrying out micro-dosing studies and crossover clinical studies, as TMDD may confound the study results and generate misleading data.…”

“…(d) Time course of hepatic HSD1 activity in SPI-62 0.7-mg and 2-mg dose groups.In these 2 dose groups, SPI-62 was given as single dose first (day 1), followed by a 6-day washout (days 1 to 6), and then 14 days QD doses (days 7 to 20). Figure3a-cwas adapted from Wu et al32 Figure3dwas adapted from Bellaire et al21…”