Abstract
BackgroundThe search for highly effective anti-malarial therapies has gathered pace and recent years have seen a number of promising single and combined therapies reach the late stages of development. A key drug development challenge is the need for early assessment of the clinical utility of new drug leads as it is often unclear for developers whether efforts should be focused on efficacy or metabolic stability/exposure or indeed whether the continuation of iterative QSAR (quantitative structure–activity and relationships) cycles of medicinal chemistry and biological testing will translate to improved clinical efficacy. Pharmacokinetic and pharmacodynamic (PK/PD)-based measurements available from in vitro studies can be used for such clinical predictions. However, these predictions often require bespoke mathematical PK/PD modelling expertise and are normally performed after candidate development and, therefore, not during the pre-clinical development phase when such decisions need to be made.MethodsAn internet-based tool has been developed using STELLA® software. The tool simulates multiple differential equations that describe anti-malarial PK/PD relationships where the user can easily input PK/PD parameters. The tool utilizes a simple stop-light system to indicate the efficacy of each combination of parameters. This tool, called OptiMal-PK, additionally allows for the investigation of the effect of drug combinations with known or custom compounds.ResultsThe results of simulations obtained from OptiMal-PK were compared to a previously published and validated mathematical model on which this tool is based. The tool has also been used to simulate the PK/PD relationship for a number of existing anti-malarial drugs in single or combined treatment. Simulations were predictive of the published clinical parasitological clearance activities for these existing therapies.ConclusionsOptiMal-PK is designed to be implemented by medicinal chemists and pharmacologists during the pre-clinical anti-malarial drug development phase to explore the impact of different PK/PD parameters upon the predicted clinical activity of any new compound. It can help investigators to identify which pharmacological features of a compound are most important to the clinical performance of a new chemical entity and how partner drugs could potentially improve the activity of existing therapies.
Highlights
The search for highly effective anti-malarial therapies has gathered pace and recent years have seen a number of promising single and combined therapies reach the late stages of development
Model validation The OptiMal-PK model was based on a validated mechanistic Pharmacokinetic and pharmacodynamic (PK/PD) model implemented in R [28] and previously published by Winter and Hastings
The results demonstrate that a single monotherapy dose of 800 or 1200 mg would be insufficient for the successful elimination of parasites in all patients and would result in recrudescence within 9 days after the treatment
Summary
The search for highly effective anti-malarial therapies has gathered pace and recent years have seen a number of promising single and combined therapies reach the late stages of development. Pharmacokinetic and pharmacodynamic (PK/PD)-based measurements available from in vitro studies can be used for such clinical predictions These predictions often require bespoke mathematical PK/PD modelling expertise and are normally performed after candidate development and, not during the pre-clinical development phase when such decisions need to be made. Lead optimization studies are used to enhance the effectiveness of the most promising compounds, it is not always apparent whether a drug’s progress is directly in line with desired TCPs or TPPs. For example, despite the availability of in vitro ADME data (absorption, disposition, metabolism and excretion) or in vivo DMPK (pharmacokinetics) studies are unable to show whether a drug’s less desirable pharmacokinetic attributes can be counter-balanced by other more desirable features such as potency. To be confident of a drug’s ultimate clinical performance, extensive in vivo experimentation or pharmacokinetic–pharmacodynamic (PK/ PD) modelling is required
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
