Abstract
PurposeThis 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.MethodsPK-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.ResultsThe 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.ConclusionsA 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.
Highlights
There is consensus among the pharmaceutical industry that improved understanding of exposure–response relationships at an early stage in the drug hunting process will be important to inform lead optimization strategies and reduce attrition rates in the clinic [1,2]
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 in vivo correlation (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 non-human primates (NHPs)
Summary
There is consensus among the pharmaceutical industry that improved understanding of exposure–response relationships at an early stage in the drug hunting process will be important to inform lead optimization strategies and reduce attrition rates in the clinic [1,2]. One can speculate that having information and knowledge of the ‘3pillars’ concepts on a development candidate can lead to better clinical hypothesis generation and early clinical development plans. Such knowledge enables the use of translatable biomarkers to facilitate clear quantitative go/no-go decisions and inform on key clinical study design questions such as dose selection and sampling times. PK-PD models are useful in characterizing exposure– response relationships where there are apparent disconnects because of temporal delays in drug action relative to drug exposure, a phenomenon referred to as hysteresis. A delay in onset and washout of action relative to drug exposure in the plasma could be due to slow distribution of the drug to and from its target site or an indirect relationship between exposure and response caused by biomarker synthesis and turnover rates or a function of the target binding kinetics [4]
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