Preface

Antimalarial drug discovery and development is a lengthy process, and given the lack of resources available for development of antimalarial drugs, discovery and development of antimalarials as single entities or combinations can take much longer than development of drugs for treatment of diseases that affect patients from first world countries. Given the limited resources for development of drugs to treat a disease not found in first world countries, drug development processes must be as efficient as possible, and expensive clinical studies must be well-planned and geared toward yielding the maximum amount of information to get the best “bang for the buck”.

Safety, comparative efficacy, and dose determination studies are all best conducted by thorough consideration of pharmacokinetic and pharmacodynamic variables that impact on how quickly all of the relevant questions can be answered to develop a drug for clinical use in man. Development of drugs to the standards to regulatory standards set by first world regulatory agencies like the FDA or EMA, in particular, imposes a high threshold that must be met with limited funds.

Well-planned clinical trials of comparative efficacy that have a sound foundation of safety and PK studies are more likely to be successful than clinical trials developed with minimal PK and safety data. The use of physiologic based pharmacokinetic/pharmacodynamic (PB PK/PD) studies, innovative population PK/PD studies, factorial study designs, and drug resistance models are all modern tools that can provide a faster path forward than simple empirical trial designs that do not utilize these techniques. The issue of malaria drug resistance in the modern era imposes yet another burden on drug developers as development of an antimalarial drug for treatment of a disease, which is difficult to begin with due to limited funds, is not a “one and done” activity. Every antimalarial drug developed to date eventually has come up against problems with drug resistance, and all of these drugs come with a limitation on their use in terms of the length of time on market until clinical resistance is encountered.

Drug combinations offer the potential to extend the life of existing antimalarial drugs, and drug combinations also have the potential to limit the development of drug resistance through disease treatment with two or more drugs whose different or synergistic mechanisms of action are mutually protective. The development and deployment of artemisinin combination therapies (ACTs), in particular, over the last decade has revolutionized malaria treatment in endemic areas. While ACTs have become the wonder drug antimalarial combination treatment of the new millennia, all ACTs on market will eventually run into drug resistance problems that preclude their use in various endemic areas. Accordingly, new and novel antimalarial drug combinations must be innovated to try and stay ahead of the growing tide of malaria drug resistance. Fundamentally, this is a contest between a parasite’s ability to mutate and man’s ability to innovate.

We believe that proper application of new, modern PK/PD tools can radically improve clinical trial design and execution which maximizes the “bang for the buck” and speeds the development of new antimalarial drug combinations.