Exploratory Translational Modeling Approach in Drug Development to Predict Human Brain Pharmacokinetics and Pharmacologically Relevant Clinical Doses

Abstract

ABSTRACT:The central nervous system (CNS) pharmacokinetics (PK) of drugs that have pharmacological targets in the brain are not often understood during drug development, and this gap in knowledge is a limitation in providing a quantitative framework for translating nonclinical pharmacologic data to the clinical patient population. A focus of translational sciences is to improve the efficiency of clinical trial design via a more judicious selection of clinical doses on the basis of nonclinical data. We hypothesize that this can be achieved for CNS-acting drugs based on knowledge of CNS PK and brain target engagement obtained in nonclinical studies. Translating CNS PK models from rat to human can allow for the prediction of human brain PK and the human dose-brain exposure relationship, which can provide insight on the clinical dose(s) having potential brain activity and target engagement. In this study, we explored the potential utility of this translational approach using rat brain microdialysis and PK modeling techniques to predict human brain extracellular fluid PK of atomoxetine and duloxetine. The results show that this translational approach merits consideration as a means to support the clinical development of CNS-mediated drug candidates by enhancing the ability to predict pharmacologically relevant doses in humans in the absence of or in association with other biomarker approaches.

Physiologically Based Pharmacokinetic Modeling to Investigate Regional Brain Distribution Kinetics in Rats

“…Due to the slow distribution from the brain tissue to the CSF, the CSF acts as a sink, causing the observed concentration gradient within the brain. This has been observed for other passively transported compounds as well (43).…”

Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations

“…The model asserts a carrier-mediated mechanism contributes to the plasma to brain transfer of both compounds. Similar to what has been done with atomoxetine and duloxetine (Kielbasa and Stratford, 2012) and clozapine and its active metabolite, N-desmethylclozapine dmd.aspetjournals.org Downloaded from (Li et al, 2014), to translate rat BBB kinetics to humans to predict human brain exposure, our approach predicts that the dopamine transporter occupancy observed in humans using PET and SPECT is due to hydroxybupropion and that the metabolite is responsible for a direct effect on increasing synaptic dopamine and norepinephrine via DAT and NET inhibition, respectively.…”

“…This approach describes plasma-to-brain transfer [bloodbrain barrier (BBB) transport], using compartmental or physiologically based pharmacokinetic modeling in animals, with subsequent coupling of measured human systemic PK with the human brain disposition derived from weight-based allometric scaling of the corresponding animal parameters (de Lange, 2013). The method has been used to predict atomoxetine and duloxetine exposure in human brain extracellular fluid (ECF) (Kielbasa and Stratford, 2012), risperidone and its metabolite (9-OH-resperidone) receptor occupancy (Kozielska et al, 2012), olanzapine receptor occupancy (Johnson et al, 2011), and receptor occupancy of clozapine and its active metabolite (N-desmethylclozapine) at multiple receptors, based on brain ECF measures using microdialysis (Li et al, 2014). In these examples, predicted exposure and/or occupancy in the human brain after subtherapeutic or therapeutic doses was accordingly congruent with in vitro receptor potency (Kielbasa and Stratford, 2012) or with receptor occupancy measured by PET imaging (Johnson et al, 2011;Kozielska et al, 2012;Li et al, 2014).…”

“…The method has been used to predict atomoxetine and duloxetine exposure in human brain extracellular fluid (ECF) (Kielbasa and Stratford, 2012), risperidone and its metabolite (9-OH-resperidone) receptor occupancy (Kozielska et al, 2012), olanzapine receptor occupancy (Johnson et al, 2011), and receptor occupancy of clozapine and its active metabolite (N-desmethylclozapine) at multiple receptors, based on brain ECF measures using microdialysis (Li et al, 2014). In these examples, predicted exposure and/or occupancy in the human brain after subtherapeutic or therapeutic doses was accordingly congruent with in vitro receptor potency (Kielbasa and Stratford, 2012) or with receptor occupancy measured by PET imaging (Johnson et al, 2011;Kozielska et al, 2012;Li et al, 2014). Thus, the objective of our study was to apply this translational approach to predict bupropion and hydroxybupropion exposure in human brain ECF, the pharmacologically relevant biophase for the purported parenchymal membrane targets.…”

Microdialysis Evaluation of Clozapine and N-Desmethylclozapine Pharmacokinetics in Rat Brain

“…In addition, application of PK scaling principles to predict human ECF concentrations from plasma exposure could also be explored. This second approach has shown promise for other CNS drugs (Kielbasa and Stratford, 2012).…”