Abstract
BackgroundModelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.MethodsIonization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS.ResultsBoth solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds.ConclusionsThis is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
Highlights
Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs
Given the importance of these two parameters as key determinants of tissue-to-plasma partitioning ratios in physiologically-based pharmacokinetic (PBPK) modelling, the results suggest that measured values for ionization constant (pKa) and Log D7.4 should be generated and used whenever possible
The work highlights the challenges that are often encountered with compounds that cover a wide range of physicochemical characteristics and emphasizes that for many of these platforms, it is unlikely that a single method format will be universally applicable to all compounds
Summary
Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. Since 2000, there has been a considerable increase in anti-malarial drug discovery leading to a relatively healthy pipeline of promising new drug candidates in preclinical and clinical development [4] Over this same time period, new drug approvals have included new artemisinin-based combinations, new combinations of other existing drugs, and new and improved formulations, each of which has contributed significantly to the anti-malarial arsenal. There have been only two new drug approvals containing new chemical entities (Synriam, a combination of the novel ozonide arterolane or OZ277 and piperaquine, and Krintafel/Kozenis containing tafenoquine) over this same period, and of these, only tafenoquine has undergone stringent regulatory approval by International Conference on Harmonization (ICH) members or observers This scenario reflects the relatively limited emphasis on anti-malarial drug discovery prior to about 2000, and the inevitable timeframe required to progress new compounds through discovery, translational and clinical development. The situation is further exacerbated by the need for combination therapies, preferably delivered in a single dose, to treat all parasitic forms and reduce the development of drug resistance, and the associated complexity of obtaining efficacy, safety, and pharmacokinetic data for individual agents before they are combined
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