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Application of Pharmacokinetic-Pharmacodynamic Modeling to Inform Translation of In Vitro NaV1.7 Inhibition to In Vivo Pharmacological Response in Non-human Primate.
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2020-09-04 , DOI: 10.1007/s11095-020-02914-9 Jeanine E Ballard 1 , Parul Pall 2 , Joshua Vardigan 2 , Fuqiang Zhao 3 , Marie A Holahan 3 , Richard Kraus 4 , Yuxing Li 4 , Darrell Henze 5 , Andrea Houghton 5 , Christopher S Burgey 6 , Christopher Gibson 1
中文翻译:
药代动力学-药效学建模在通知非人类灵长类动物体内NaV1.7抑制体内药理反应的翻译中的应用。
更新日期:2020-09-04
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2020-09-04 , DOI: 10.1007/s11095-020-02914-9 Jeanine E Ballard 1 , Parul Pall 2 , Joshua Vardigan 2 , Fuqiang Zhao 3 , Marie A Holahan 3 , Richard Kraus 4 , Yuxing Li 4 , Darrell Henze 5 , Andrea Houghton 5 , Christopher S Burgey 6 , Christopher Gibson 1
Affiliation
Purpose
This work describes a staged approach to the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling in the voltage-gated sodium ion channel (NaV1.7) inhibitor drug discovery effort to address strategic questions regarding in vitro to in vivo translation of target modulation.Methods
PK-PD analysis was applied to data from a functional magnetic resonance imaging (fMRI) technique to non-invasively measure treatment mediated inhibition of olfaction signaling in non-human primates (NHPs). Initial exposure-response was evaluated using single time point data pooled across 27 compounds to inform on in vitro to in vivo correlation (IVIVC). More robust effect compartment PK-PD modeling was conducted for a subset of 10 compounds with additional PD and PK data to characterize hysteresis.Results
The pooled compound exposure-response facilitated an early exploration of IVIVC with a limited dataset for each individual compound, and it suggested a 2.4-fold in vitro to in vivo scaling factor for the NaV1.7 target. Accounting for hysteresis with an effect compartment PK-PD model as compounds advanced towards preclinical development provided a more robust determination of in vivo potency values, which resulted in a statistically significant positive IVIVC with a slope of 1.057 ± 0.210, R-squared of 0.7831, and p value of 0.006. Subsequent simulations with the PK-PD model informed the design of anti-nociception efficacy studies in NHPs.Conclusions
A staged approach to PK-PD modeling and simulation enabled integration of in vitro NaV1.7 potency, plasma protein binding, and pharmacokinetics to describe the exposure-response profile and inform future study design as the NaV1.7 inhibitor effort progressed through drug discovery.中文翻译:
药代动力学-药效学建模在通知非人类灵长类动物体内NaV1.7抑制体内药理反应的翻译中的应用。