Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary Absorption, Systemic Distribution, and Oral Absorption.

BACKGROUND AND OBJECTIVES: Physiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib. METHODS: A PBPK model was built in GastroPlus® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution. RESULTS: The inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state. CONCLUSIONS: Fully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

Cytopathological review of cervical pathology: Impact for women and follow-up results.

BACKGROUND: Cervical screening programs have had an important effect on the reduction of cervical cancer rates. Comprehensive programs require access to pathological review to improve the sensitivity of screening cytology and the specificity of diagnostic histology. AIMS: To determine the number of cases where cervical cytology or histology was amended at cytopathological review; whether amendments were 'upgrades' or 'downgrades', and how amendments aligned with follow-up results for these patients. MATERIALS AND METHODS: A retrospective cohort study was performed of all patients reviewed from January 2016 to December 2017 (n = 287 cases, from 254 patients) at colposcopy multidisciplinary meetings at Wellington Hospital, a tertiary referral hospital. Where amendments to cytology or histology were made, follow-up results were retrieved where available (85.7% and 84.2% respectively). RESULTS: Cytology or histology was amended in 24.7% of cases. Smear cytology was amended in 16.7%. Where cytology was upgraded (n = 9), 44% had subsequent results of equal or higher grade including one case of adenocarcinoma. Where cytology was downgraded (n = 19), 93.8% (81.9-100%) had follow-up studies showing equal or lower results. Cervical biopsy histology was amended in 12.2% of cases (upgraded n = 19, downgraded n = 6). Large loop excision of the transformation zone or cone biopsy histology was amended in three cases (7.9%). CONCLUSIONS: Cytopathological review appears to improve the specificity of the comprehensive cervical screening program, leading to a reduction in unnecessary treatment. Additionally, a small number of cases of malignant or premalignant disease were detected.