Dr Stephen Brand, MMV Associate Director of Drug Discovery, Dr Peter Webborn, Independent DMPK & PK/ PD Consultant, and Prof. Dennis Smith, DMPK expert and ESAC member, discuss MMVSola, the MMV 2022 Project of the Year.
1. How does MMVSola contribute to antimalarial drug discovery?
Dr Stephen Brand: In essence, it predicts human PK from preclinical data and combines it with malaria pharmacodynamics to predict antimalarial doses.
Dr Peter Webborn: Using MMVSola, you can predict what dose of a novel compound is likely to be effective in patients based on preclinical information. MMVSola also calculates a range of PK parameters such as half-life and bioavailability.1 Together, these allow you to ask “what if” questions like “What would be the impact if we improved this parameter twofold?” And that really helps to focus on the key issues in the design of new long-lasting molecules.
2. Why was MMVSola introduced, and what has been its impact?
Prof. Dennis Smith: Teams traditionally moved compounds through various stages of the drug discovery process using cut-off values for potency, selectivity,2 solubility, and at later stages in vivo3 parameters such as clearance,4 half- life and bioavailability. But these were often considered in isolation. The key lessons come from combining all these properties, and this requires not only new computational tools, but also systematic collection of the right data. MMVSola holistically links all the relevant preclinical data into a simple property: the effective dose. The benefits of its use across MMV discovery projects, which are conducted at a diverse range of research centres, are substantial.
- Ability to focus on clinical efficacy from an early stage;
- Alignment of methodology, data recording and use in order to achieve common standards; and
- Holistic use of the data so multiple parameters can be balanced correctly against desired clinical outcome.
The development of regular user group workshops has considerably broadened discovery teams’ knowledge and expertise, facilitating universal uptake of the tool.
3. Who has been involved in the delivery of MMVSola?
Dr Stephen Brand: This project has been a real team effort. The key point is that MMVSola required expertise in several different areas. There’s DMPK, which is about being able to predict human exposure for a compound. There are pharmacodynamic studies using data from a laboratory model of malaria.5 PK/PD modelling is about combining those data to predict the dose needed to have a desired effect in humans. Then there’s computer programming and software design for implementing this methodology as a usable tool. Finally, there’s an expert group that trains MMV discovery teams to use the tool and interpret the information.
4. How does MMVSola help discovery teams?
Dr Peter Webborn: MMVSola enables teams to evaluate early in a project what the predicted doses of their compounds are, without needing a PK/PD modeller on the team. If it turns out that predicted doses are too high, which they usually are in early stages of lead optimization,6 it lets them get a handle on which parameters will be the most impactful to optimize, so they can adopt an appropriate medicinal chemistry strategy.
5. How have you and your team further developed this tool since its launch?
Dr Peter Webborn: We’ve added a few new modules recently after discussions with the users. One is enabling allometric scaling7 to be used to predict clearance. We’ve also added the ability to incorporate renal clearance8 in human predictions.
Dr Stephen Brand: Another important new functionality is the prediction of a prophylactic (or chemoprevention) dose. It’s a different way of defining how much drug you need: the tool originally focused on the dose you would need to kill all the blood-stage parasites in someone with malaria. The prophylactic dose is about achieving concentrations above what’s called the minimum inhibitory concentration9 to provide protection for as long as 28 days. MMVSola calculates how much drug you would need to get above that level for that amount of time.
6. What are your plans for future upgrades?
Dr Stephen Brand: We will continually assess MMVSola’s performance and will apply preclinical and clinical data from future compounds to update the tool’s algorithms and improve predictions. We are also aiming to enhance the user interface and to develop this tool to be able to make dose predictions for other diseases, using the expertise within the MMV network and IntiQuan – while of course maintaining it as an open-access resource.
7. How do I access MMVSola?
Dr Stephen Brand: It’s available at the web address (https://www.mmvsola.org), and it’s free of charge, secure and does not retain data. Training and user group workshops are provided regularly and are also free of charge.10
1. Half-life is the time needed for the amount of drug in the body to decrease by half. Bioavailability is the amount of an administered drug that enters the circulation and can therefore have a pharmacological effect.
2. How closely the compound’s effects are focused on the proteins it is meant to target in the malaria parasite.
3. Obtained within a living organism.
4. How rapidly a drug is eliminated from the body.
5. Jiménez-Díaz MB et al. “Improved Murine Model of Malaria Using Plasmodium falciparum Competent Strains and Non-Myelodepleted NOD-scid IL2Rγnull Mice Engrafted with Human Erythrocytes” Antimicrob Agents Chemother. 53(10):4533-6 (2009), doi: 10.1128/AAC.00519-09
6. Lead optimization is the modification of identified lead molecules to improve their target specificity and selectivity (i.e., to confirm desired effects on the target and minimize potential undesired effects) and PK while preserving their desired activity on their targets.
7. Allometric scaling uses relationships between body size and physical, anatomical and biochemical changes (which tend to be slower in larger organisms) to predict human dose and exposure based on results in animals.
8. How fast a substance is removed from the body by the kidneys.
9. The lowest concentration able to inhibit growth of the parasite.
10. If you would like a demonstration or training in the use of MMVSola, please contact Stephen Brand at email@example.com.