Development, evaluation and application of an in silico model for antimalarial drug treatment and failure

Pharmacological 'mechanism based' modeling is refined and used to develop an in silico model of antimalarial drug treatment validated against clinical and field data. We used this approach to investigate key features of antimalarial drug action and effectiveness, with emphasis on the current generation of artemisinin combination therapies. We conclude: (i) The development of artemisinin tolerance and resistance will, unless checked, have an immediate, large impact on the protection afforded to its partner drug, and on likely clinical efficacy of artemisinin combination therapies. (ii) Long follow-up periods are required in clinical trials to detect all drug failures; follow-up periods of 28 days recommended by the World Health Organization are likely to miss at least 50% of drug failures and we confirm recent suggestions that 63 days would be a more appropriate follow-up period. (iii) Day seven serum drug concentrations are a significant risk factor of failure. Although, paradoxically, receiver operating characteristic curve analysis reveals their predictive power is relatively poor. (iv) The pharmacokinetic properties of the partner drugs in ACTS are the most important determinant of treatment outcome, particularly it's maximum killing rate. We discuss the assumptions made in such modeling approaches and how similar approaches may be refined in future work.