OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimensReport as inadecuate

OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimens - Download this document for free, or read online. Document in PDF available to download.

Malaria Journal

, 15:344

First Online: 07 July 2016Received: 07 March 2016Accepted: 17 June 2016DOI: 10.1186-s12936-016-1401-8

Cite this article as: Aljayyoussi, G., Kay, K., Ward, S.A. et al. Malar J 2016 15: 344. doi:10.1186-s12936-016-1401-8


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.

KeywordsPK-PD modelling Malaria Plasmodium Pharmacokinetics Artemisinin Drug discovery Pre-clinical Medicinal chemistry Lead optimisation ADMET DMPK AbbreviationsADMETabsorption, disposition, metabolism, excretion and toxicity





DMPKdisposition, metabolism and pharmacokinetics

ICinhibitory concentration

MPCminimum parasitic concentration



PMRparasite multiplication ratio

PRRparasite reduction ratio

MPCminimum parasitic concentration

kaabsorption rate

keelimination rate

QSARquantitative structure–activity and relationships

T1-2elimination half-life

TCPtarget candidate profile

TPPtarget product profile

Vmaxmaximal kill rate

Vdvolume of distribution

Download fulltext PDF

Author: Ghaith Aljayyoussi - Katherine Kay - Stephen A. Ward - Giancarlo A. Biagini

Source: https://link.springer.com/

Related documents