Pharmacokinetic modeling of CNS disposition of 5-HT<sub>3</sub> receptor antagonist with quantitative assessment of the role of P-glycoprotein efflux
Creators: name: Chiang, Manting
Publisher: name: No Publisher Supplied
Year: 2020

description: Neuropathic pain is a chronic pain condition that affects 7-10% of the general population. The currently available treatments are often unable to provide sufficient pain relief for the patients or are prescribed at doses that produce toxic side effects. Emerging research highlights the potential for serotonin subtype receptor 3 (5-HT3) antagonists, such as ondansetron, as novel treatment strategies for reducing pain symptoms. However, current clinical reports are conflicting on whether ondansetron truly reduces pain symptoms in patients. One of the driving hypotheses is that there is insufficient drug exposure at the site of action needed to produce sustainable and significant pain relief in patients. The thesis focused on developing quantitative approaches to evaluate central nervous system (CNS) exposure of the 5-HT3 antagonist, ondansetron. In the introductory Chapter 1, an overview of neuropathic pain, the serotonergic pathway in pain transmission, 5-HT3 as a pharmacological target for neuropathic pain treatment, CNS physiology, and general pharmacokinetic (PK) knowledge is provided. In Chapter 2, a pharmacokinetic study was completed in wild-type and P-glycoprotein (Pgp) knock-out male and female rats to evaluate plasma and brain, spinal cord, and CSF concentrations after intravenous administration of ondansetron. The study provided quantitative assessment of the role of Pgp in limiting ondansetron exposure in various regions of the CNS, when comparing WT and Pgp KO rats. Slight differences were observed in ondansetron pharmacokinetics and CNS disposition between male and female animals. A semi-physiological model was developed and successfully captured the data in all tissues for all experimental groups. Chapter 3 wild-type male and female rats were co-administered tariquidar, a specific Pgp inhibitor, with ondansetron. Plasma and CNS results were compared with the previously obtained results from Chapter 2. Our results showed that tariquidar administration at 7.5 mg/kg resulted in complete inhibition of Pgp efflux of ondansetron in brain and spinal cord. There was also an effect of tariquidar on plasma disposition for ondansetron, which may not be dependent on Pgp inhibition. A semi-physiological model successfully described the pharmacokinetics of ondansetron in animals receiving ondansetron and tariquidar, as well as the wild-type and knock-out animals simultaneously. Proposed modeling framework could serve as the base to further analysis of the potential use of Pgp inhibitors in enhancing delivery of 5HT3 receptor antagonists to the CNS. In Chapter 4, a population PK study is presented describing the plasma and cerebrospinal fluid (CSF) disposition of ondansetron in patients. Serial plasma and single CSF samples were collected from 14 patients, in addition to patient demographic information such as creatinine clearance and age. A two-compartmental PK model was built to describe plasma disposition with an additional CSF compartment, describing CSF disposition with a single KP term. In Chapter 5, ondansetron pharmacokinetics was evaluated using a physiologically based pharmacokinetic model (PBPK) model, as well as an allometric model. A full-body PBPK model was constructed to simulate plasma, brain, and CSF profiles and quantify the impact of Pgp efflux of ondansetron on the BBB. An allometric model was constructed to scale ondansetron disposition across rat, cat, cynomolgus monkey, and human. Collectively, the modeling strategies emphasize the impact of Pgp efflux of ondansetron in CNS disposition, and the opportunity of inhibiting Pgp to explore the therapeutic efficacy of ondansetron for neuropathic pain treatment.